Dissertations / Theses on the topic 'Gastrointestinal system Diseases Australia'

Crohn’s disease (CD) and ulcerative colitis (UC) constitute the two major forms of inflammatory bowel disease (IBD), which are disorders of chronic inflammation in the gastrointestinal tract that are associated with significant morbidity and socioeconomic burden. IBD patients with long-standing intestinal inflammation are more prone to developing colorectal cancer (CRC). Until now, none of the existing IBD treatments is able to heal the mucosal ulcerations satisfactorily. The endocannabinoid system (ECS), which comprises of endogenous cannabinoid ligands, their receptors, and metabolic enzymes, has been implicated in gut homeostasis, visceral sensation, inflammation and gastrointestinal motility. Available studies in rodent models of IBD suggest that enhancing the ECS tone may reduce inflammation and improve mucosal integrity. This evidence indicates that the components of the ECS seem well positioned to exert a protective role in IBD and also to offer a great opportunity for therapeutic exploitation. Despite the role of the ECS in the gut, the presence and function of the components of the ECS is not well characterised in human IBD. The primary aim of the study was to investigate the state of the major components of the ECS in human IBD and to establish whether IBD is associated with any changes of the components of the ECS. Cannabinoid CB1 and CB2 receptors, enzymes for endocannabinoid biosynthesis PLC, “LRAT”, NAPE-PLD and DAGL, and endocannabinoid metabolic enzymes FAAH and MAGL were analysed from colonic tissue samples of CD, UC and control patients by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) to determine the relative mRNA expression of the above genes. The RT-qPCR analysis showed that the mRNA expression of PLC, LRAT, and NAPE-PLD were unchanged in both CD and UC, whiles DAGL mRNA was decreased in UC but was unchanged in CD. The endocannabinoid degradation enzymes, FAAH mRNA expression was also unchanged in CD but decreased in UC, whereas the mRNA expression of MAGL was significantly decreased in both CD and UC. NAPE-PLD/FAAH and DAGL/MAGL ratios, an estimation of the balance of AEA and 2-AG levels, showed that AEA and 2-AG levels could be increased and unchanged, respectively, in IBD. The mRNA expression of CB1 was significantly decreased in CD and UC whilst CB2 mRNA expression was unchanged in both forms of IBD. The study demonstrated that the components of the ECS which were investigated were present in colonic tissues of both IBD patients and healthy individuals, but they appear to be off balance in CD and UC patients. The decreased CB1 receptors in IBD patients could be an important modifier in the disease and could also provide a possible pathoaetiological mechanism linking IBD and CRC. Although these findings look promising, more studies with larger sample size are required to characterise the components of the ECS in human IBD.

This research examined trends in gastrointestinal infections in tropical and subtropical regions over an 11-year period in Queensland. Higher rates were confirmed of Campylobacter and Salmonella GI infections in tropical than in temperate regions with rates increasing over time in both regions and an increased relative risk when the mean daily temperature exceeded temperature thresholds. The increased risk continued for up to 5 days after the index "heat" day, but the maximum effect was observed two days after the heat event. However, a significant association between heatwaves and GI infections in a same time period could not be identified.

Helicobacter pylori (H.pylori) had been confirmed by the World Health Organization (WHO) as Group 1 carcinogens, in which it has been identified to be related with the development of gastric carcinoma. Gastroesophageal reflux disease (GERD) is less commonly found in Asia, while the number of H.pylori infection is considerably to be higher than that of the Western population. The relationship between H.pylori and GERD still remains ambiguous nowadays. One of the contributing factors affecting the level of gastric secretion might be due to the genetic cause. The aim of this review is to assess whether the current first-line therapy on GERD would be effective or not in relieving the symptoms of the patients with H.pylori infection.
published_or_final_version
Community Medicine
Master
Master of Public Health

Pancreatic cancer (PC) is the fourth leading cause of cancer death in Western societies. Despite significant progress in understanding the molecular pathology of PC and its precursor lesion: pancreatic intraepithelial neoplasia (PanIN), there remain no molecules with proven clinical utility. Affymetrix Genechipfi oligonucleotide microarrays were used to interrogate mRNA expression of PC and normal pancreas to identify molecular pathways dysregulated in PC. Analysis of these data identified altered expression of numerous components of the S100 Calcium Binding Protein Family, Retinoic Acid signalling pathway and the HOX transcriptional network in PC compared to normal pancreas. These pathways were assessed using immunohistochemistry (IHC) and in-situ hybridisation (ISH) in a cohort of patients with PC. Increased protein expression, of S100A2, S100A6 and S100P was observed in 43%, 60% and 48% of PC respectively. Expression of S100A2 was associated with a poor outcome (p = 0.009), whilst increased expression of S100A6 (p = 0.0008) and S100P (p = 0.0005) were associated with an improved outcome. Additionally, S100A2 expression was identified as an independent marker of outcome in resected tumours. Aberrant expression of retinoic acid signalling components was demonstrated in PC cell lines using semi-quantitative RT-PCR. ISH demonstrated expression of Retinoic Acid Induced 3 (RAI3), an orphan G protein coupled receptor normally expressed in the fetal lung, in 68% of PC, and this co-segregated with an improved overall survival (p = 0.026).Ectopic protein expression of HOXB2, a transcription factor normally expressed in the developing hindbrain and modulated by retinoic acid, was observed in 15% of early PanIN lesions and 38% of PC specimens. Expression of HOXB2 was associated with non-resectable tumours and was an independent predictor of poor survival in resected tumours. Suppression of HOXB2 protein expression using small interfering RNA, resulted in epithelioid trans-differentiation in the Panc-1 PC cell line, however no alteration in proliferation rates were observed compared to controls. This thesis has shown that transcript profiling and tissue validation has identified potential markers of early diagnosis and outcome in PC. Furthermore, pathways and molecules previously thought to be associated with normal human development have been implicated to play a role in the development and progression of PC. Further analyses of these markers will determine any potential role in future diagnostic and therapeutic strategies.

Resumo: O presente trabalho foi delineado para investigar a freqüência de infecção pelo Helicobacter em cães oriundos do Biotério Central da UNESP - Campus de Botucatu - e a incidência da espécie Helicobacter pylori(Hp) nos animais. Os animais utilizados foram capturados em várias cidades, desconhecendo-se seus hábitos alimentares até a captura, mas é provável que foram pertencentes ou conviveram com pessoas de classe sócio-econômica de baixo poder aquisitivo, onde a incidência de Hp em seres humanos é mais elevada. Foram utilizados os métodos de teste rápido da urease, teste imunocromatográfico (kit H. pylori one step teste) e o método histoquímico de coloração pelo Giemsa. A coleta de material foi feita em 109 caninos sem raça definida, sendo 49 machos e 60 fêmeas. O sangue foi retirado da veia jugular e as amostras gástricas e duodenais foram obtidas por endoscopia (61/109) e pela técnica aberta (48/109). As análises, pelo teste rápido da urease e coloração pelo Giemsa, mostraram que, em 97,96% dos machos (48/49) e em 100% das fêmeas (60/60), foi detectada reação positiva para Helicobacter, sendo 99,08% (108/109) na totalidade dos animais. Não foram observadas alterações estatisticamente significativas entre os dois sexos... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: The present work was delineated to investigate the infection frequency for Helicobacter in dogs originating from Central Animal House of UNESP - Campus of Botucatu - and the incidence of the species pylori in the animals. The used animals were captured in several towns, being ignored their alimentary habits until the capture, but it is probable that they belonged or they lived together with people of socioeconomic class of low purchasing power, where the incidence of H. pylori in humans is higher. The methods used were of fast urease test, immunocromatograph test (kit H. pylori one step test) and histochemical coloration method for Giemsa. The material collection was made in 109 mongrel dogs, being 49 males and 60 females. The blood was removed of the jugular vein and the gastric and duodenal samples were obtained by endoscopy (61/109) and by the open technique (48/109). The analyses for the fast test of the urease and coloration for Giemsa showed that, in 97,96% of the males (48/49) and in 100% of the females (60/60), positive reaction was detected for Helicobacter, being 99,08% (108/109) in the totality of the animals. No statistically significant alterations significant were observed between the two sexes... (Complete abstract, click electronic address below)
Orientador: Luiz Eduardo Naresse
Coorientador: Rogério Saad Hossne
Mestre

Made available in DSpace on 2014-06-11T19:25:25Z (GMT). No. of bitstreams: 0 Previous issue date: 2012-02-29Bitstream added on 2014-06-13T20:13:51Z : No. of bitstreams: 1 carvalho_kim_me_botib.pdf: 473702 bytes, checksum: cf335e6c7efaff94811da0dd6fc60b36 (MD5)
Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
A úlcera péptica é causada por um desequilíbrio entre os fatores protetores e lesivos da mucosa. A expansão global no consumo de álcool e DAINEs têm contribuído para um aumento da incidência da doença na população. Um dos maiores problemas relativo à úlcera péptica consiste na recidiva da mesma após a terapêutica, justificando-se a busca por novos tratamentos mais eficazes. Relatos científicos mostram que os óleos essenciais derivados das plantas possuem uma variedade de atividades biológicas, tais como ansiolíticos, antioxidantes, antiinflamatórios e antiulcerogênicos. Baseando-se nessa premissa resolvemos avaliar a atividade gastroprotetora do monoterpeno geraniol. Os resultados do estudo mostraram que o geraniol na dose de 7,5 mg/Kg foi efetivo no modelo de úlcera induzida por etanol absoluto com 70% de proteção. Essa ação gastroprotetora mostrou-se dependente da presença de óxido nítrico, dos grupamentos sulfidrilas e do aumento na produção de muco gástrico. No modelo de úlcera gástrica induzida por indometacina o geraniol não teve ação antiulcerogênica, sugerindo-se que a proteção desse monoterpeno esteja associada à metabólitos da via da COX, tais como: as prostaglandinas. No modelo de úlcera induzida por etanol em ratos pré-tratados com indometacina, os resultados indicaram que a gastroproteção do geraniol está relacionada com as PGs, uma vez que na presença de um inibidor da COX, ele perdeu sua proteção. Os dados apontam ainda para uma atividade antioxidante, comprovada no modelo de isquemia e reperfusão, onde o geraniol conferiu uma proteção à mucosa gástrica de 71%, e no modelo de úlcera duodenal induzida por cisteamina cuja proteção observada foi de 68%. No modelo de ligadura de piloro observou-se a ausência de atividade antisecretória gástrica e verificou-se...
A peptic ulcer is caused by an imbalance between the protective and the agressive factors of the mucosa. The global expansion in the consumption of alcohol and NSAIDs have contributed to an increased incidence of disease in the population. One of the biggest problems relative on peptic ulcer is recurrence of it after the treatment, justifying the search for new more effective treatments. Scientific reports show that essential oils derived from plants have a variety of biological activities, such as anxiolytics, antioxidants, anti-inflammatory and antiulcerogenics. Based on this assumption we decided to evaluate the gastroprotective activity of the monoterpene geraniol. The study results showed that geraniol at a dose of 7.5 mg/Kg was effective in the model of ulcer induced by absolute ethanol with 70% protection. This gastroprotective action was dependent on the presence of nitric oxide, sulfhydryl groups (SHs) and increased production of gastric mucus. In the model of gastric ulcer indomethacin-induced geraniol (7.5 mg / kg) did not had antiulcerogenic action, suggesting that protection this monoterpene is associated with metabolites of the COX pathway, such as prostaglandins. In the model of ethanol-induced ulcer in rats pretreated with indomethacin the results indicated that the geraniol's gastroprotection is related to the prostaglandins, since in the presence of a COX inhibitor, it lost its protection. The results also point to an antioxidant activity, proven in the model of ischemia and reperfusion, where geraniol gave a protection to the gastric mucosa of 71% and the model of duodenal ulcer cysteamine-induced whose protection observed was 68%. In the pylorus ligation model was observed the absence of gastric antisecretory activity and was verified through the model of activated charcoal that this monoterpene... (Complete abstract click electronic access below)

Orientador: Clélia Akiko Hiruma-Lima
Banca: Marcos José Salvador
Banca: Luiz Claudio Di Stasi
Resumo: A úlcera péptica é causada por um desequilíbrio entre os fatores protetores e lesivos da mucosa. A expansão global no consumo de álcool e DAINEs têm contribuído para um aumento da incidência da doença na população. Um dos maiores problemas relativo à úlcera péptica consiste na recidiva da mesma após a terapêutica, justificando-se a busca por novos tratamentos mais eficazes. Relatos científicos mostram que os óleos essenciais derivados das plantas possuem uma variedade de atividades biológicas, tais como ansiolíticos, antioxidantes, antiinflamatórios e antiulcerogênicos. Baseando-se nessa premissa resolvemos avaliar a atividade gastroprotetora do monoterpeno geraniol. Os resultados do estudo mostraram que o geraniol na dose de 7,5 mg/Kg foi efetivo no modelo de úlcera induzida por etanol absoluto com 70% de proteção. Essa ação gastroprotetora mostrou-se dependente da presença de óxido nítrico, dos grupamentos sulfidrilas e do aumento na produção de muco gástrico. No modelo de úlcera gástrica induzida por indometacina o geraniol não teve ação antiulcerogênica, sugerindo-se que a proteção desse monoterpeno esteja associada à metabólitos da via da COX, tais como: as prostaglandinas. No modelo de úlcera induzida por etanol em ratos pré-tratados com indometacina, os resultados indicaram que a gastroproteção do geraniol está relacionada com as PGs, uma vez que na presença de um inibidor da COX, ele perdeu sua proteção. Os dados apontam ainda para uma atividade antioxidante, comprovada no modelo de isquemia e reperfusão, onde o geraniol conferiu uma proteção à mucosa gástrica de 71%, e no modelo de úlcera duodenal induzida por cisteamina cuja proteção observada foi de 68%. No modelo de ligadura de piloro observou-se a ausência de atividade antisecretória gástrica e verificou-se... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: A peptic ulcer is caused by an imbalance between the protective and the agressive factors of the mucosa. The global expansion in the consumption of alcohol and NSAIDs have contributed to an increased incidence of disease in the population. One of the biggest problems relative on peptic ulcer is recurrence of it after the treatment, justifying the search for new more effective treatments. Scientific reports show that essential oils derived from plants have a variety of biological activities, such as anxiolytics, antioxidants, anti-inflammatory and antiulcerogenics. Based on this assumption we decided to evaluate the gastroprotective activity of the monoterpene geraniol. The study results showed that geraniol at a dose of 7.5 mg/Kg was effective in the model of ulcer induced by absolute ethanol with 70% protection. This gastroprotective action was dependent on the presence of nitric oxide, sulfhydryl groups (SHs) and increased production of gastric mucus. In the model of gastric ulcer indomethacin-induced geraniol (7.5 mg / kg) did not had antiulcerogenic action, suggesting that protection this monoterpene is associated with metabolites of the COX pathway, such as prostaglandins. In the model of ethanol-induced ulcer in rats pretreated with indomethacin the results indicated that the geraniol's gastroprotection is related to the prostaglandins, since in the presence of a COX inhibitor, it lost its protection. The results also point to an antioxidant activity, proven in the model of ischemia and reperfusion, where geraniol gave a protection to the gastric mucosa of 71% and the model of duodenal ulcer cysteamine-induced whose protection observed was 68%. In the pylorus ligation model was observed the absence of gastric antisecretory activity and was verified through the model of activated charcoal that this monoterpene... (Complete abstract click electronic access below)
Mestre

Thesis (PhD)--Stellenbosch University, 2014.
ENGLISH ABSTRACT: Background: Irritable bowel syndrome (IBS) is a common gastrointestinal (GI) disorder. GI symptoms and impaired quality of life affect between 10-20% of all adults, corresponding to about 25-50% of all patients who visit a gastroenterologist’s clinic. In recent years, several novel mechanisms of IBS that likely relate to previously established theories have been identified. Inflammation, postinfectious low-grade inflammation, immunological and genetic predisposition along with altered microbiota are critical in IBS development, while several dietary factors may also play a role in this syndrome. However, none of these factors accounts for the full repertoire of IBS symptoms, and the pathophysiology of this condition is not fully understood. The overarching aim of this study was to investigate the nutrient intakes, GI microbiota and the effect of Lactobacillus plantarum (L.plantarum) 299v in IBS patients. Sub-aims: 1) Update healthcare professionals on current probiotic information and provide an overview of probiotic treatment approaches, with special emphasis on IBS, 2) conduct a well designed randomised, double blind, placebo-controlled trial (RCT) with L. plantarum 299v as part of an intervention and establish whether a course of probiotics may alleviate undesirable symptoms of IBS and improve quality of life, 3) assess nutrient intake in patients with irritable bowel syndrome (IBS) compared to dietary recommendations, 4) validate and assess the reproducibility of food records and 5) identify possible nutrient risk components for establishing GI microbiota involved in IBS and as part of an intervention, determine whether a course of probiotics may alter stool microbiota. Results: 1) A review article published by the author provides an overview of current probiotic treatment options to health care professionals and indicates certain probiotics are a promising therapeutic treatment option for management of IBS symtpoms, 2) the effects of the single strain probiotic, L. plantarum 299v, supplementation was evaluated in a RCT. Compared to placebo, the probiotic supplementation showed no significant reduction in GI symptom severity scores, particularly abdominal pain relief. Quality of life was also not improved in the treatment versus control group. Both the treatment and placebo groups improved significantly over the trial period, indicating a large placebo effect, 3) nutrient intakes of the IBS patients compared to current dietary reference recommendations indicates that this group of patients are at risk for nutrient inadequacies in key macro and micronutrients, 4) the validity and reliability of the dietary data showed good reliability but poor validity as measured by plasma fatty acids and 5) the GI microbiota composition in the phenotypically different diarrhoea-predominant IBS (D-IBS) vs. constipation-predominant IBS (C-IBS) showed that D-IBS patients had significantly lower counts of Lactobacillus plantarum compared to C-IBS patients. The probiotic had no significant effects on the GI microbiota as measured by quantitative polymerase chain reaction (qPCR). It was found that nutrient intakes had a significant impact on the microbiota. Lower fibre intakes were associated with higher Bacteroides spp., lower Bifidobacteria bifidum and Lactobacillus plantarum counts in both IBS groups. Conclusion: Taken together, L.plantarum 299v did not alleviate the GI symptoms of IBS, nor was it associated with significant changes in the GI microbiota. IBS patients may be at risk of key nutrient inadequacies. The influence of nutrient intakes on the GI microbiota provides an attractive explanation as a potential pathophysiological factor for IBS.
AFRIKAANSE OPSOMMING: Agtergrond: Prikkelbare derm-sindroom (PDS) is ‘n algemene gastro-intestinale (GI) stoornis. GI simptome affekteer die lewenskwaliteit van 10-20% van alle volwassenes. Dit stem ooreen met ongeveer 25-50% van alle pasiënte wat ‘n gastroënteroloog konsulteer. Verskeie oorspronklike meganismes vir die ontwikkeling van PDS is onlangs identifiseer. Inflammasie, post-infektiewe lae-graadse inflammasie, immunologiese en genetiese vatbaarheid tesame met veranderde mikrobiota is krities vir die ontwikkeling van PDS. Sekere dieetfaktore mag ook bydraend wees tot hierdie sindroom. Geen van hierdie faktore is egter verantwoordelik vir die volle spektrum van PDS simptome nie en die patofisiologie van die toestand word ook nog nie ten volle verstaan nie. Die oorkoepelende doel van hierdie studie is om nutriëntinname, GI mikrobiota en die uitwerking van L.plantarum 299v in PDS pasiënte bepaal. Sub-doelwitte: 1) Om gesondheidswerkers in te lig aangaande die nuutste inligting oor probiotika en om ‘n oorsig van probiotika behandelingsopsies te verskaf, met spesiale klem op PDS, 2) om ‘n goed beplande ewekansige, dubbel-blinde, plasebo-beheerde kliniese studie met L.plantarum 299v as deel van die intervensie uit te voer om sodoende te bepaal of ‘n kursus probiotika ongewensde simptome van PDS kan verbeter en lewenskwaliteit sodoende verhoog, 3) om nutriëntinname in pasiënte met PDS te bepaal vergeleke met dieet aanbevelings, 4) om die geldigheid en herhaalbaarheid van voedselrekords te bepaal en 5) om moontlike nutriënt risikokomponente vir die ontwikkeling van GI mikrobiota betrokke in PDS te identifiseer en om as deel van ‘n intervensie te bepaal of ‘n kursus probiotika stoelgang mikrobiota patrone verander. Resultate: 1) ‘n Oorsigartikel gepubliseer deur die kandidaat dui probiotika aan as ‘n belowende terapeutiese opsie in die behandeling van PDS simptome, 2) die effek van ‘n enkelstam probiotikum, L.plantarum 299v, is evalueer deur ‘n ewekansige, dubbel-blinde, plasebo-beheerde kliniese studie. Vergeleke met die plasebo, het probiotiese aanvulling geen betekenisvolle vermindering in die GI simptome in PDS pasiënte tot gevolg gehad nie. Lewenskwaliteit het ook nie verbeter in die behandelde versus die kontrole groep nie. Beide die behandelde en plasebo groepe het aansienlik verbeter oor die studietydperk, wat ‘n groot plasebo effek aandui, 3) nutriëntinname van die PDS groep vergeleke met huidige dieetaanbevelings, dui daarop dat hierdie groep pasiënte ‘n risiko het vir die ontwikkeling van kern nutriënttekorte (makro- en mikronutriënte), 4) die geldigheid en betroubaarheid van die dieetdata dui op goeie betroubaarheid, maar swak geldigheid soos bepaal deur plasma vetsure en 5) die dermkanaal mikrobiotiese samestelling in die verskillende fenotipes, diarree-oorheersende PDS (D-PDS) vs. konstipasie-oorheersende PDS (K-PDS) dui daarop dat D-PDS pasiënte aansienlike minder Lactobacillus plantarum gehad het vergeleke met K-PDS pasiënte. Die probiotikum het geen beduidende uitwerking op die oorheersende mikrobiota gehad nie, soos gemeet deur kwantitatiewe polimerase kettingreaksie (kPKR). Daar is gevind dat dieet ‘n beduidende impak op die mikrobiota gehad het. Daar is ‘n verband tussen laer vesel inname en hoёr Bacteroides spp. en laer Bifidobacteria bididum en Lactobacillus plantarum tellings gevind in beide PDS groepe. Gevolgtrekking: Die L.plantarum 299v enkelstam probiotikum het nie die gastrointestinale simptome van PDS pasiënte verlig nie en daar is ook geen beduidende veranderinge in die mikrobiota gevind nie. PDS pasiënte mag ‘n verhoogde risiko toon vir kern nutriënttekorte. Die invloed van nutriëntinname op GI mikrobiota verskaf ‘n belowende verduideliking as ‘n potensiële patofisiologiese faktor in PDS.

Doctor of Philosophy
All surveillance systems are based on an effective general surveillance system because this is the system that detects emerging diseases and the re-introduction of disease to a previously disease free area. General surveillance requires comprehensive coverage of the population through an extensive network of relationships between animal producers and observers and surveillance system officers. This system is under increasing threat in Australia (and many other countries) due to the increased biomass, animal movements, rate of disease emergence, and the decline in resource allocation for surveillance activities. The Australian surveillance system is state-based and has a complex management structure that includes State and Commonwealth government representatives, industry stakeholders (such as producer bodies) and private organisations. A developing problem is the decline in the effectiveness of the general surveillance system in the extensive (remote) cattle producing regions of northern Australia. The complex organisational structure of surveillance in Australia contributes to this, and is complicated by the incomplete capture of data (as demonstrated by slow uptake of electronic individual animal identification systems), poorly developed and integrated national animal health information systems, and declining funding streams for field and laboratory personnel and infrastructure. Of major concern is the reduction in contact between animal observers and surveillance personnel arising from the decline in resource allocation for surveillance. Fewer veterinarians are working in remote areas, fewer producers use veterinarians, and, as a result, fewer sick animals are being investigated by the general surveillance system. A syndrome is a collection of signs that occur in a sick individual. Syndromic surveillance is an emerging approach to monitoring populations for change in disease levels and is based on statistical monitoring of the distribution of signs, syndromes and associations between health variables in a population. Often, diseases will have syndromes that are characteristic and the monitoring of these syndromes may provide for early detection of outbreaks. Because the process uses general signs, this method may support the existing (struggling) general surveillance system for the extensive cattle producing regions of northern Australia. Syndromic surveillance systems offer many potential advantages. First, the signs that are monitored can be general and include any health-related variable. This generality provides potential as a detector of emerging diseases. Second, many of the data types used occur early in a disease process and therefore efficient syndromic surveillance systems can detect disease events in a timely manner. There are many hurdles to the successful deployment of a syndromic surveillance system and most relate to data. An effective system will ideally obtain data from multiple sources, all data will conform to a standard (therefore each data source can be validly combined), data coverage will be extensive (across the population) and data capture will be in real time (allowing early detection). This picture is one of a functional electronic data world and unfortunately this is not the norm for either human or animal heath. Less than optimal data, lack of data standards, incomplete coverage of the population and delayed data transmission result in a loss of sensitivity, specificity and timeliness of detection. In human syndromic surveillance, most focus has been placed on earlier detection of mass bioterrorism events and this has concentrated research on the problems of electronic data. Given the current state of animal health data, the development of efficient detection algorithms represents the least of the hurdles. However, the world is moving towards increased automation and therefore the problems with current data can be expected to be resolved in the next decade. Despite the lack of large scale deployment of these systems, the question is becoming when, not whether these system will contribute. The observations of a stock worker are always the start of the surveillance pathway in animal health. Traditionally this required the worker to contact a veterinarian who would investigate unusual cases with the pathway ending in laboratory samples and specific diagnostic tests. The process is inefficient as only a fraction of cases observed by stock workers end in diagnostic samples. These observations themselves are most likely to be amenable to capture and monitoring using syndromic surveillance techniques. A pilot study of stock workers in the extensive cattle producing Lower Gulf region of Queensland demonstrated that experienced non-veterinary observers of cattle can describe the signs that they see in sick cattle in an effective manner. Lay observers do not posses a veterinary vocabulary, but the provision of a system to facilitate effective description of signs resulted in effective and standardised description of disease. However, most producers did not see personal benefit from providing this information and worried that they might be exposing themselves to regulatory impost if they described suspicious signs. Therefore the pilot study encouraged the development of a syndromic surveillance system that provides a vocabulary (a template) for lay observers to describe disease and a reason for them to contribute their data. The most important disease related drivers for producers relate to what impact the disease may have in their herd. For this reason, the Bovine Syndromic Surveillance System (BOSSS) was developed incorporating the Bayesian cattle disease diagnostic program BOVID. This allowed the observer to receive immediate information from interpretation of their observation providing a differential list of diseases, a list of questions that may help further differentiate cause, access to information and other expertise, and opportunity to benchmark disease performance. BOSSS was developed as a web-based reporting system and used a novel graphical user interface that interlinked with an interrogation module to enable lay observers to accurately and fully describe disease. BOSSS used a hierarchical reporting system that linked individual users with other users along natural reporting pathways and this encouraged the seamless and rapid transmission of information between users while respecting confidentiality. The system was made available for testing at the state level in early 2006, and recruitment of producers is proceeding. There is a dearth of performance data from operational syndromic surveillance systems. This is due, in part, to the short period that these systems have been operational and the lack of major human health outbreaks in areas with operational systems. The likely performance of a syndromic surveillance system is difficult to theorise. Outbreaks vary in size and distribution, and quality of outbreak data capture is not constant. The combined effect of a lack of track record and the many permutations of outbreak and data characteristics make computer simulation the most suitable method to evaluate likely performance. A stochastic simulation model of disease spread and disease reporting by lay observers throughout a grid of farms was modelled. The reporting characteristics of lay observers were extrapolated from the pilot study and theoretical disease was modelled (as a representation of newly emergent disease). All diseases were described by their baseline prevalence and by conditional sign probabilities (obtained from BOVID and from a survey of veterinarians in Queensland). The theoretical disease conditional sign probabilities were defined by the user. Their spread through the grid of farms followed Susceptible-Infected-Removed (SIR) principles (in herd) and by mass action between herds. Reporting of disease events and signs in events was modelled as a probabilistic event using sampling from distributions. A non-descript disease characterised by gastrointestinal signs and a visually spectacular disease characterised by neurological signs were modelled, each over three outbreak scenarios (least, moderately and most contagious). Reports were examined using two algorithms. These were the cumulative sum (CuSum) technique of adding excess of cases (above a maximum limit) for individual signs and the generic detector What’s Strange About Recent Events (WSARE) that identifies change to variable counts or variable combination counts between time periods. Both algorithms detected disease for all disease and outbreak characteristics combinations. WSARE was the most efficient algorithm, detecting disease on average earlier than CuSum. Both algorithms had high sensitivity and excellent specificity. The timeliness of detection was satisfactory for the insidious gastrointestinal disease (approximately 24 months after introduction), but not sufficient for the visually spectacular neurological disease (approximately 20 months) as the traditional surveillance system can be expected to detect visually spectacular diseases in reasonable time. Detection efficiency was not influenced greatly by the proportion of producers that report or by the proportion of cases or the number of signs per case that are reported. The modelling process demonstrated that a syndromic surveillance system in this remote region is likely to be a useful addition to the existing system. Improvements that are planned include development of a hand-held computer version and enhanced disease and syndrome mapping capability. The increased use of electronic recording systems, including livestock identification, will facilitate the deployment of BOSSS. Long term sustainability will require that producers receive sufficient reward from BOSSS to continue to provide reports over time. This question can only be answered by field deployment and this work is currently proceeding.

Functional constipation (FC) is a major gastrointestional (GI) disorder which affects about 14% population worldwide. However, due to efficacy and safety concerns, more than 50% FC patients are not completely satisfied with current conventional therapies, thus alternative therapies are needed. A substantial part of FC patients have symptom of slow colonic motility, while therapy targeting a single pathway cannot benefit all of them. In this thesis, we searched for novel FC therapeutics from two distinct sources, both of which can improve colonic motility significantly: (1) MaZiRenWan (MZRW), an herb formula from Traditional Chinese Medicine (TCM); and (2) Spexin (SPX), a newly identified neuropeptide that is deregulated in FC. On the basis of efficacy validation for MZRW by randomized, placebo-controlled clinical studies, we investigated the bioactive compounds and pharmacological actions of MZRW. Firstly, a machine-learning based method, namely MOST, was developed to relate bioactive compounds with their mechanism-of-action targets. MOST demonstrated good performance in 7-fold cross-validation (over 87% accuracy) and temporal validation (over 76% accuracy). In the case laxative effect, MOST predicted that acetylcholinesterase (ACHE) was the mechanism-of-action target of aloe-emodin; in vivo studies validated this prediction. Secondly, we analyzed the bioactive compounds and mechanism-of-actions of MZRW with combination of UPLC-QTOF-MS/MS, clustering analysis, organ bath, and MOST approaches. 97 compounds were identified in MZRW extract, and 35 of them can be found in plasma and feces samples of rats with oral administration of MZRW. Chemical space analysis suggested that these compounds can be classified into component groups, while the corresponding pharmacology can be studied with representative compounds. Emodin, amygdalin, albiflorin, honokiol, and naringin were shown to induce spontaneous contractions of rat colonic smooth muscle in vitro. Biological targets in ACh-, estrogen-, prostaglandin-, cannabinoid-, and purine signaling pathways are able to explain the prokinetic effects of representative compounds and component groups. Pharmacological actions of MZRW are mixture of five classic paradigms. Thirdly, the latest results of three-armed, randomized and controlled clinical study showed that MZRW demonstrated comparable efficacy with the first line drug Senna, the first line drug for constipation in HK, during treatment period, both were better than placebo; and the efficacy was more sustainable in follow-up period when comparing that of Senna and placebo. These data suggested the unique pharmacological profile of MZRW for FC. With pharmacometabolomic analysis, we found that change of oleamide is negatively correlated (pearson r = -0.59, p<0.001) with improvement of Complete Spontaneous Bowel Movement (CSBM) in MZRW group, but not in Senna or placebo group. Oleamide is up-regulated in FC patients compared with healthy controls, and MZRW can significantly reduce oleamide in FC patients (n=30), healthy human volunteers (n=23), and in normal mice (n=12) serum, ileum, and colon. The regulation of oleamide by MZRW is possibly via augmenting FAAH-mediated degradation. Lastly, we investigated the possibility to use SPX, the newly identified, FC-associated neuropeptide to change GI motility. The deregulation of SPX has been found in several disorders including FC, however, the metabolic instability of SPX prevent it to be directly used in clinical practices. Our investigation through combination of molecular dynamics (MD) simulations and NMR analysis suggested a β-turn-helix-β-turn (βαβ) conformation for human spexin (hSPX) adopts in solution. Consistent with this conformation, cyclic analogues of hSPX with a disulfide bond between residue 1 and 13, LH101 (CWTPQAMLYLKGCQ-NH2), activated both GalR2 (EC50=1.19 μM) and GalR3 (EC50=1.56 μM) with potency comparable to wild type, and that the acetylation at the N-terminal, LH101(Ac) raises the potency EC50=0.38 μM on GalR2 and EC50=0.39 μM on GalR3. The serum half lives of LH101 (t1/2=355.7 min) and LH101(Ac) (t1/2=1973.7 min) were significantly longer than the wild type (t1/2=66.5 min), and LH101(Ac) induces the contractions of mice intestinal segment in vitro and attenuates the oleamide-induced slow GI motility in vivo. Collectively, our studies in MZRW suggested that estrogen and oleamide signaling pathways are potential new targets to develop novel therapeutics for FC, while lead compounds targeting these pathways could be found from MZRW. The final study suggested CSAs have potential to be developed as new FC therapy by targeting the galanin receptor associated pathway.

El perfil de seguridad de los antiinflamatorios no esteroideos (AINE) ha sido ampliamente estudiado y tanto los efectos terapéuticos como los efectos secundarios a nivel gastrointestinal (GI) y cardiovascular, se han asociado históricamente con el efecto inhibidor de los mismos sobre la COX-1 y la COX- 2 respectivamente. Este enfoque, en cuanto a efectos GI se refiere, ha quedado obsoleto, ya que ahora hay evidencias de la participación de múltiples vías celulares en el daño GI mediado por AINE y aunque no se conoce la secuencia exacta, dichas vías estarían relacionadas, entre otros, con el estado oxidativo o redox del enterocito. Las terapias clásicas para evitar los daños GI se basan en el uso de inhibidores de la bomba de protones (IBP) que disminuyen la secreción ácida y aunque el pH ácido está directamente relacionado con el daño GI, ya que lo agrava, no se trata de la causa principal que genera los efectos GI secundarios de esta familia de medicamentos. Además, la hipoclorhidria y aclorhidria se relacionan con un mayor riesgo de infecciones entéricas por diferentes microorganismos patógenos y diferentes estudios han identificado cambios profundos en el microbioma intestinal en pacientes tratados con IBP lo que según estudios recientes tendría implicaciones directas en el organismo y una repercusión mayor en el estado de salud de lo que se conocía. Por otro lado, la melatonina ha demostrado ser un potente agente antioxidante, numerosos estudios avalan tanto su interacción directa con RL y moléculas oxidantes, como su efecto indirecto al activar otros sistemas enzimáticos de defensa contra el daño oxidativo. Dadas las evidencias sobre la actividad antioxidante de la MLT, el objetivo global planteado en la presente tesis doctoral ha sido el estudio de la MLT como posible agente preventivo del daño GI inducido por los AINE. Esta tesis está relacionada con diversas áreas de conocimiento, en primer lugar, con la Biofarmacia y Farmacocinética, necesarias para el desarrollo de un modelo ex vivo con el cual evaluar procesos de absorción intestinal. A través de este método puede evaluarse la permeabilidad de fármacos a través de intestino delgado, así como predecirse cambios en la misma. La Histología y Biología celular necesarias para la evaluación de lesiones en los distintos tejidos estudiados; por último, la Bioquímica para determinar niveles de marcadores celulares bioquímicos, que permitan dilucidar posibles mecanismos de acción involucrados en la prevención del daño GI mediado por la MLT.

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A epidemiologia das infecções por nematódeos gastrintestinais foi avaliada em ovinos criados em Botucatu - SP. A partir de abril de 2008 até março de 2011, dois cordeiros traçadores foram expostos à infecção natural por nematódeos gastrintestinais durante 28 dias consecutivos, ao pastejar junto com um rebanho de ovelhas. Haemonchus contortus apresentou as maiores intensidades de infecção com prevalência de 100%. Não houve influência significativa das estações do ano na intensidade de infecção por H. contortus. Trichostrongylus colubriformis também apresentou prevalência de 100% com a intensidade de infecção menor durante os meses de verão. No caso de T. colubriformis, houve correlação significativa entre as contagens de vermes x precipitação (r = -0,32; P < 0,05). Outras três espécies de nematódeos foram verificadas, no entanto, em pequenas quantidades, prevalências e intensidades de infecção: Oesophagostomum columbianum 28% (25,2), Cooperia curticei 7% (4,5) e Trichuris spp. 2 % (1). Contudo, as condições ambientais da área foram favoráveis durante todo o ano para a transmissão de H. contortus e T. colubriformis. Este fato explica parcialmente o fracasso de programas governamentais e privados realizados no intuito de promover a ovinocultura no Estado, devido a taxas elevadas de mortalidade e baixa produtividade causada pela verminose
The epidemiology of gastrointestinal nematode infections was evaluated in sheep raised in Botucatu – SP. Every month, from April 2008 until March 2011, two tracer lambs were exposed to natural infection with gastrointestinal nematodes for 28 consecutive days, while grazing together with a sheep flock. Haemonchus contortus presented the highest infection intensities with 100% prevalence. There was no significant influence of the seasons in H. contortus infection intensity. Trichostrongylus colubriformis also presented 100% prevalence with the lowest infection intensity during the summer months. In the case of T. colubriformis, there was significant correlation coefficient between worm counts x precipitation (r = -0.32; P < 0.05). Other three nematodes species were found in tracer lambs, however, in small numbers. Their prevalence and mean intensity of infection (in parenthesis) were the following: Oesophagostomum columbianum 28% (25.2), Cooperia curticei 7% (4.5) and Trichuris spp. 2% (1). In conclusion, the environmental conditions of the area were very favourable for H. contortus and T. colubriformis transmission all year round. These explain in part the failure of private and governmental programs to promote the sheep breeding activity in São Paulo State due to high sheep mortality rates and low productivity caused by gastrointestinal nematode infections

Orientador: Alessandro Francisco Talamini do Amarante
Banca: Raimundo de Souza Lopes
Banca: Fernanda Rosalinski Moraes
Resumo: A epidemiologia das infecções por nematódeos gastrintestinais foi avaliada em ovinos criados em Botucatu - SP. A partir de abril de 2008 até março de 2011, dois cordeiros traçadores foram expostos à infecção natural por nematódeos gastrintestinais durante 28 dias consecutivos, ao pastejar junto com um rebanho de ovelhas. Haemonchus contortus apresentou as maiores intensidades de infecção com prevalência de 100%. Não houve influência significativa das estações do ano na intensidade de infecção por H. contortus. Trichostrongylus colubriformis também apresentou prevalência de 100% com a intensidade de infecção menor durante os meses de verão. No caso de T. colubriformis, houve correlação significativa entre as contagens de vermes x precipitação (r = -0,32; P < 0,05). Outras três espécies de nematódeos foram verificadas, no entanto, em pequenas quantidades, prevalências e intensidades de infecção: Oesophagostomum columbianum 28% (25,2), Cooperia curticei 7% (4,5) e Trichuris spp. 2 % (1). Contudo, as condições ambientais da área foram favoráveis durante todo o ano para a transmissão de H. contortus e T. colubriformis. Este fato explica parcialmente o fracasso de programas governamentais e privados realizados no intuito de promover a ovinocultura no Estado, devido a taxas elevadas de mortalidade e baixa produtividade causada pela verminose
Abstract: The epidemiology of gastrointestinal nematode infections was evaluated in sheep raised in Botucatu - SP. Every month, from April 2008 until March 2011, two tracer lambs were exposed to natural infection with gastrointestinal nematodes for 28 consecutive days, while grazing together with a sheep flock. Haemonchus contortus presented the highest infection intensities with 100% prevalence. There was no significant influence of the seasons in H. contortus infection intensity. Trichostrongylus colubriformis also presented 100% prevalence with the lowest infection intensity during the summer months. In the case of T. colubriformis, there was significant correlation coefficient between worm counts x precipitation (r = -0.32; P < 0.05). Other three nematodes species were found in tracer lambs, however, in small numbers. Their prevalence and mean intensity of infection (in parenthesis) were the following: Oesophagostomum columbianum 28% (25.2), Cooperia curticei 7% (4.5) and Trichuris spp. 2% (1). In conclusion, the environmental conditions of the area were very favourable for H. contortus and T. colubriformis transmission all year round. These explain in part the failure of private and governmental programs to promote the sheep breeding activity in São Paulo State due to high sheep mortality rates and low productivity caused by gastrointestinal nematode infections
Mestre

Synthesis of Cys-containing peptides has long been posed as an attractive challenge for peptide chemist. Protecting groups for the nucleophilic beta-thiol group of Cys residues must be stable during peptide elongation, and can be removed under mild conditions when necessary. Synthesis of peptides with multiple-disulfide bonds frequently demands the implementation of additional orthogonal dimensions into the protection schemes. Therefore, combinations of orthogonal and/or compatible protecting groups for each pair of Cys residues enable the regioselective formation of disulfide bridges. The development and study of novel protecting groups for the side-chain of the Cys residue may increase the number of synthetic tools for the efficient synthesis of Cys-containing peptides. The solid-phase strategy has been applied for the preparation of small, medium-sized peptides. Nevertheless, the elongation of large peptide sequences through a stepwise solid-phase peptide synthesis is limited and convergent strategies, such as fragment condensation approach should be adopted. The preparation of fully protected peptide fragments on solid phase for convergent synthesis calls for handles with maintain intact the side-chain protecting groups upon cleavage. The present thesis has focused on the development and application of novel orthogonal strategies for the synthesis of complex peptides, including Cys-containing peptides and long and difficult peptide sequences by fragment condensation approach. Specifically, different Cys-protecting groups have been evaluated and a handle has been designed and developed.
Recientemente, el péptido linaclotide ha sido aprobado por la Food and Drug Administration (FDA) y por la European Medicines Agency (EMA) para el tratamiento de enfermedades gastrointestinales tales como el estreñimiento crónico (EC) y el síndrome del intestino irritable (SII)1. Linaclotide es administrado oralmente, y es un potente agonista selectivo del receptor de la guanilato ciclasa tipo C (GC-C) localizado en el intestino. Desde un punto de vista estructural, este péptido de cadena corta presenta un elevado número de residuos de cisteínas que le confieren una conformación bien definida debido a la presencia de tres enlaces disulfuro intramoleculares entre los residuos Cys1-Cys6, Cys2-Cys10 y Cys5-Cys13. El diseño y la optimización de una estrategia sintética eficiente para la obtención de cantidades que permitan satisfacer el mercado en un futuro, se presenta como un reto debido a la presencia de sus tres puentes disulfuro. Para la optimización de dicha síntesis es fundamental establecer y discutir sus dos principales limitaciones: el riesgo de racemización de los residuos de cisteína durante la síntesis lineal de la cadena peptídica; y el posterior plegamiento y formación de los enlaces disulfuros correctamente. Se diseñaron y estudiaron diversas estrategias regioselectiva, semi-regioselectiva y se exploró la posibilidad de preparar el péptido linaclotide siguiendo una estrategia aleatoria, utilizando un esquema de protección de los residuos de cisteína no selectivo. La elección de los grupos protectores del grupo tiol de las cisteínas, su posición en la secuencia, la influencia de los grupos protectores vecinos, además del orden de plegamiento y formación de los enlaces disulfuro fueron objeto de estudio. Finalmente, el péptido completamente plegado y oxidado se analizó detenidamente con el fin de confirmar que la conectividad establecida entre los residuos de cisteína coincidían con los enlaces disulfuro nativos presentes en Linaclotide.

Functional gastrointestinal disorders (FGIDs) continue to be the most common disorders treated in gastroenterological practice. They are associated with higher levels of psychological distress, impaired quality of life and increased healthcare use. The main objective of the current thesis was to evaluate the level of discrepancy (i.e., incongruence) between patients and physicians quality of life, as well as the effect this has on psychological distress, physician satisfaction and quality of life. More specifically, we explored the effect of incongruence in a primary care setting and compared this between two patient groups: patients with an FGID diagnosis and patients with an organic diagnosis. In order to pursue our main objective, two studies were carried out. The first study involved a systematic review examining the potential benefits of short-term educational interventions. The second study was a cross sectional mixed-methods study that aimed to explore the differences that exist between incongruent and diagnostic groups in relation to psychological distress, physician satisfaction and quality of life. This also involved assessing the aforementioned variables whilst taking into account other variables that could potentially be moderating the relationship. The final part of the study involved implementing a qualitative approach which consisted of focus groups with patients and semi-structured interviews with physicians. The results from the first study indicated that short educational programmes could benefit both patients and physicians, yet there still appears to be limited research regarding effective programmes that specifically target symptom severity and quality of life of patients. Furthermore, training and intervention opportunities for physicians are still relatively sparse leading to difficulties when assisting patients in practice. The findings from the analyses conducted with incongruence as a dichotomised variable showed that both incongruence and diagnosis contribute to psychological distress. Patients in the incongruent group had higher scores on psychological distress than congruent patients. On the other hand, no significant differences were found between incongruent and congruent patients in relation to physician satisfaction levels. Patients with an FGID diagnosis had higher scores on psychological distress and lower physician satisfaction levels than patients with an organic diagnosis. The results from the analyses carried out with incongruence as a continuous variable supported this further. Statistically significant positive correlations were found for incongruence with psychological distress and age. Female patients and patients with an FGID diagnosis had higher levels of psychological distress and worse quality of life, as well as lower physician satisfaction in the case of patients with an FGID diagnosis. A statistically significant positive correlation was found only for physician satisfaction and age. When carrying out multiple regression models, we found that gender and incongruence had the greatest influence on psychological distress. Finally, from the moderation models we found that only age was a significant moderator between incongruence and psychological distress. From the qualitative part of the research, five major themes were found when conducting a thematic analysis: (1) Illness, Emotional and Personal Problems (2) Disease- Healthcare System Interaction (3) Health system (4) Intervention and (5) Patients. From the patient focus groups key factors were outlined as needing to be addressed such as the overload of the healthcare system and long waiting lists. From the physician interviews we identified that a lack of resources and a clear referral pathway to mental health services may be contributing to the difficulties when treating these patients. To our knowledge, this is the first study to investigate the influence of incongruence in primary healthcare settings using this procedure. Additionally, as far as we are aware this is also the first study to explore the underlying reasons for incongruence using a qualitative approach.
Los trastornos gastrointestinales funcionales (TGF) siguen siendo los trastornos más habituales tratados en la práctica gastroenterológica. Están asociados con los niveles más altos de distrés psicológico, deterioro de la calidad de vida y un mayor uso de la atención médica. El objetivo principal de la tesis fue evaluar el nivel de discrepancia (es decir, la incongruencia) entre la percepción de pacientes y médicos sobre la calidad de vida del paciente y el efecto que esto tiene sobre el distrés psicológico, la satisfacción con el médico y la calidad de vida. Más específicamente, exploramos el efecto de la incongruencia en un entorno de atención primaria y lo comparamos entre dos grupos de pacientes; pacientes con diagnóstico de TGF y pacientes con diagnóstico orgánico. Los resultados del primer estudio indicaron que los programas educativos breves podrían beneficiar tanto a los pacientes como a los médicos, sin embargo, todavía parece haber bibliografía limitada con respecto a programas efectivos que se enfoquen específicamente en la gravedad de los síntomas y la calidad de vida de los pacientes. Los hallazgos de los análisis realizados con la incongruencia mostraron que tanto la incongruencia como el diagnóstico contribuyen el distrés psicológico. Los resultados de los análisis cuantitativos adicionales respaldaron esto aún más, además en estos se encontraron correlaciones positivas estadísticamente significativas para la incongruencia con el distrés psicológico y la edad. Las pacientes del sexo femenino y los pacientes con diagnóstico de TGF presentaron mayores niveles del distrés psicológico y peor calidad de vida, además de menor satisfacción con el médico que en el caso de los pacientes con diagnóstico TGF. De la parte cualitativa de la investigación, se encontraron cinco grandes tópicos al realizar un análisis temático; (1) Enfermedad, problemas emocionales y personales (2) Interacción enfermedad-sistema sanitario (3) Sistema sanitario (4) Intervención y (5) Pacientes. Hasta donde sabemos, este es el primer estudio que investiga la influencia de la incongruencia en los entornos de atención primaria de la salud utilizando este procedimiento. Además, este es también el primer estudio que explora las razones subyacentes de la incongruencia utilizando un enfoque cualitativo.

[Truncated abstract] Indigenous Australians suffer cardiovascular disease (CVD) at a rate six times greater than the general population in Australia and while the incidence of CVD has been reduced dramatically amongst the majority of non-indigenous Australians and amongst Indigenous populations in other countries in the last 30 years, there has been little change in the figures for Aboriginal Australians, showing that heart health campaigns have little impact, for this group of people. Aims : The principal aims of this study were firstly, to determine and record the barriers to the development and delivery of CVD prevention programs amongst Indigenous Australians and secondly, to develop an alternative, effective and culturally sensitive method of delivering heart health messages. Methods and results : The study was qualitative research undertaken in three South-West towns of Western Australia where the incidence of CVD was high amongst the Aboriginal community members. The use of semi-formal interviews, informal individual consultation, observation, and focus groups were methods implemented to obtain information. The first phase of the research was to identify the barriers which affected the Aboriginal Health Workers’ ability to deliver specialist educational programs. Questionnaires and interviews with the Aboriginal Health Workers and other health professionals in the towns, and community focus groups were undertaken in this phase of the study. The second phase of the research was aimed at developing an alternative strategy for delivering heart health messages. The focus changed to adopt more traditional ways of passing on information in Indigenous communities. The idea of small gatherings of friends or family with a trusted community member presenting the health message was developed. The third phase of the research was to implement this new approach. Lay educators who had been identified within focus groups and by Aboriginal Health Workers were trained in each of the towns and a protocol involving discussions of health issues, viewing a video on CVD, produced by the National Heart Foundation, sharing in a ‘heart healthy’ lunch and partaking in a ‘heart health’ knowledge game which was developed specifically for the gatherings. Several of these gatherings were held in each of the towns and they became known as ‘HeartAware parties’.

The use of immunoglobulin G N-glycomics to study chronic non-communicable disorders and other complex phenotypes emerged following the Human Genome Project. The consortium discovered that most phenotypes were too complex to be explained by genetics alone. Thus, the biological importance of epigenetics was recognised; heritable modifications to gene expression rather than the genome itself. Nglycosylation is a form of epigenetic regulation known as a post-translational modification. It stabilises the immunoglobulin G structure and alters downstream responses elicited by the antibody and is extensively studied as a candidate biomarker in the post-genomic era. The N-glycosylation of immunoglobulin G itself is complex, with glycosyltransferases and glycosylhydrolases influencing the biosynthesis of the branching structures. Moreover, altered N-glycosylation is associated with an array of phenotypes. Our research team considers the N-glycome as an interphenotype of subclinical health status; an amalgamation of genetic predisposition, environmental exposure and health behaviours over the life-course. This underscores the value of the immunoglobulin G N-glycome in the shift towards predictive, preventive and personalised medicine. However, there is still considerable heterogeneity even among individuals with the same disorder, which warrants further investigation to improve precision of the biomarker. This thesis aimed to determine the degree the underlying genome and clinical factors explain the heterogeneity of the immunoglobulin G N-glycome. I used a subset of the cross-sectional population-based Busselton Healthy Ageing Study (n=637, 54.0% female, 46.2 to 68.3 years of age). The participants represent a highly homogenous population (99% identify as Caucasian with Caucasian parents), and all noninstitutionalised ‘Baby-boomers’ (adults born between 1946 and 1964) listed on the electoral roll in the City of Busselton between 2010 and 2016 were eligible to participate. Three studies were designed to address the thesis aim. Firstly, previous IgG-related genetic polymorphisms were successfully validated using association studies of the N-glycan features. Secondly, next-generation sequencing of leucocyte mRNA was modelled with the N-glycome. Differentially expressed genes were identified, as well as the implementation of a multivariate model to integrate the ‘omics datasets. Finally, clinical factors and health behaviours were modelled using various statistics, extending on previous research. Collectively, however, the three studies evidenced potential utility of the immunoglobulin G N-glycome in identifying cardiometabolic disorders and associated risk factors. A polymorphism with genome-wide significance had pleiotropy to type 2 diabetes mellitus. Additionally, the clinical studies correlated cardiometabolic risk factors (central adiposity, blood pressure, C-reactive protein, triglycerides, fasting blood glucose and insulin) as well as the health behaviours excessive alcohol consumption and current smoking status (both associated with increased risk of cardiometabolic disorders) to an increase in pro-inflammatory immunoglobulin G glycoforms, thus potentiating involvement of immunoglobulin G in the pathophysiology of these phenotypes. Overall, this data-driven thesis identified several factors explaining immunoglobulin G N-glycome heterogeneity. These should be considered in subsequent translational research, to improve the precision of this complex biomarker when stratifying populations of interest.

Мета: Оцінити якість життя та стан автономної нервової системи у хворих на неускладнену артеріальну гіпертензію (АГ) в залежності від наявності супутнього кислото залежного захворювання(КЗЗ) шлунково-кишкового тракту (ШКТ).

by Ng Chung Ying Davy.
Thesis (M.Phil.)--Chinese University of Hong Kong, 1994.
Includes bibliographical references (leaves 91-103).
ACKNOWLEDGMENT --- p.1
ABSTRACT --- p.2
Chapter CHAPTER 1 : --- INTRODUCTION --- p.3
Chapter CHAPTER 2 : --- LITERATURE REVIEW --- p.5
Chapter 2.1. --- The History of Laser --- p.5
Chapter 2.1.1 --- Pre-Maser History (1917 - 1952) --- p.5
Chapter 2.1.2. --- The Development of the Maser (1953 - 1959) --- p.6
Chapter 2.1.3. --- The Development of the Laser (1960 - 1961) --- p.7
Chapter 2.1.4. --- Expanding the Laser Concept (1962 - 1966) --- p.8
Chapter 2.1.5. --- New Laser Development (1967 - at present) --- p.11
Chapter 2.2. --- Basic Laser System --- p.11
Chapter 2.2.1. --- The Active Laser Media --- p.12
Chapter 2.2.2. --- The Source of Excitation Energy --- p.12
Chapter 2.2.3. --- A Febry-Perot Interferometer --- p.13
Chapter 2.3. --- Basic operational principles of laser --- p.13
Chapter 2.4. --- Characteristics of Laser Radiation --- p.14
Chapter 2.5. --- Laser Reactions in Living Tissue --- p.15
Chapter 2.5.1. --- Laser Interactions with the Eye --- p.15
Chapter 2.5.2. --- Laser Interaction with the Skin and its Appendages --- p.16
Chapter 2.5.3. --- Laser Interaction with other tissues --- p.16
Chapter 2.6. --- Thermal Effect of Laser Irradiation of Living Tissues --- p.20
Chapter 2.7. --- Medical lasers and their applications --- p.21
Chapter 2.7.1. --- Neodymium-doped yttrium-aluminium- garnet (Nd:YAG) laser --- p.21
Chapter 2.7.2. --- Argon laser --- p.21
Chapter 2.7.3. --- Carbon dioxide laser --- p.22
Chapter 2.7.4. --- Tunable dye laser --- p.22
Chapter 2.7.5. --- Gold Vapour Laser --- p.23
Chapter 2.7.6. --- Copper Vapour Laser --- p.23
Chapter 2.8. --- Port-wine stains --- p.24
Chapter 2.8.1. --- Pathology of port-wine stains --- p.24
Chapter 2.8.2. --- Treatment of port-wine stains by lasers --- p.24
Chapter 2.9. --- Laser Therapy in the Gastrointestinal Tract --- p.28
Chapter 2.10. --- Esophageal varices --- p.30
Chapter 2.10.1. --- Etiology of oesophageal varices --- p.30
Chapter 2.10.2. --- Pathology of oesophageal varices --- p.31
Chapter 2.10.3. --- Diagnosis of esophageal varices --- p.31
Chapter 2.10.4. --- Treatment of esophageal varices --- p.33
Chapter CHAPTER 3 : --- ANIMAL EXPERIMENTS --- p.42
Chapter 3.1. --- General Materials --- p.42
Chapter 3.1.1. --- Equipment --- p.43
Chapter 3.1.2. --- Drugs and chemical --- p.47
Chapter 3.1.3. --- Laboratory Animals --- p.48
Chapter 3.1.4. --- Surgical Instruments --- p.49
Chapter 3.1.7. --- Disposable --- p.49
Chapter 3.1.8. --- Sutures --- p.49
Chapter 3.1.9. --- Histopathological Preparation --- p.50
Chapter 3.2. --- Experiment 1 : Iatrogenic perforation of the rat's stomach by the continues application of the Copper Vapour Laser at different power level --- p.51
Chapter 3.2.1. --- Introduction --- p.51
Chapter 3.2.2. --- Methods --- p.52
Chapter 3.2.3. --- Results --- p.55
Chapter 3.2.4. --- Discussion --- p.60
Chapter 3.3. --- Experiment 2 : Obliteration of the rats' mesenteric vein with the Copper Vapour Laser --- p.61
Chapter 3.3.1. --- Introduction --- p.61
Chapter 3.3.2. --- Method --- p.62
Chapter 3.3.3. --- Results --- p.63
Chapter 3.3.4. --- Discussion --- p.65
Chapter CHAPTER 4 : --- CONCLUSION --- p.67
REFERENCES --- p.91

My placement for the Master of Philosophy in Applied Epidemiology (MAE) degree was with the Zoonoses, Foodborne and Emerging Infectious Diseases section (ZoFE), within the Office of Health Protection, Australian Government Department of Health. This placement has allowed me to apply the skills and knowledge of the epidemiology of infectious diseases acquired throughout my degree. I focused on the following four core projects. My review of the National Enhanced Listeriosis Surveillance System (NELSS) found that it had been invaluable in listeriosis surveillance in Australia since 2010. It has been used not only to detect clusters and outbreaks but has also assisted in the identification and investigation of possible sources of these outbreaks. NELSS is viewed as valuable with a high level of acceptability by the users of the system, despite limitations including a lack of understanding of system capabilities, duplication of data entry and the system not storing all available data. This review highlights the effectiveness of enhanced surveillance for a foodborne disease, though improvements are needed. In 2013 I was part of a team that investigated an outbreak of foodborne gastroenteritis linked to a buffet meal served at a Canberra restaurant. The cohort study and environmental and laboratory investigations suggested that a breakdown in cleanliness, temperature control and food handling practices resulted in contamination of the buffet food. Our investigation resulted in public health actions, such as repairs to the kitchen of the implicated restaurant, staff training and the development of food business management plans, to limit the potential for such an outbreak to occur in the future. As there is no reliable treatment for Australian Bat lyssavirus (ABLV) or rabies virus infection upon the onset of symptoms, treatment must occur as either pre or post-exposure prophylaxis. The National Human Rabies Immunoglobulin Database records information of people who have received Human Rabies Immunoglobulin (HRIg) in Australia as part of post-exposure prophylaxis treatment. Between 1 January 2010 and 31 December 2013, 3,003 individuals received HRIg for potential exposures to ABLV or rabies virus. A third received HRIg due to potential exposures to ABLV occurring in Australia. The current messaging for the risks of ABLV infection from bats in Australia should be reviewed and revised to ensure that it is appropriately targeted and effective. Two thirds of people received HRIg for potential exposures to the rabies virus overseas. Most occurred in Indonesia and most due to exposure to monkeys. We need to continue to warn of the risk of potential exposure to rabies virus when travelling overseas, particularly to Indonesia. Q fever is a zoonosis that has a wide range of reservoirs in Australia. In humans the disease can manifest as either acute febrile illness or chronic illness that may affect the heart or liver. The Australian Government funded the National Q fever Management Program (NQFMP) from 2000 to 2006, which provided screening and vaccination for target high risk groups. We found notified Q fever cases were predominately male, aged 40 to 59 years, who resided in Queensland or New South Wales. Interestingly the age of notified Q fever cases and the proportion of cases that were female both increased over time. It may be time to re-evaluate the at-risk groups recommended for Q fever vaccination as per the Australian Immunisation Handbook. Additionally, there may be a place for an agreed and consistent enhanced dataset for collection at the jurisdictional level or at the national level to better understand the epidemiology of Q fever in Australia.

Bibliography: leaves 181-233.
233 p. : ill. ; 30 cm.
Investigates pharmacological control of transient lower oesophagal sphincter relaxations as a treatment of gastro-oesophageal reflux. Two major classes of pharmaceutical agents were explored; anticholinergic agents and the GABAb agonist, baclofen.
Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1999

Inadequate delivery of nutrition to the critically ill is common, and may adversely affect clinical outcomes, including survival. This thesis reports studies designed to characterise the gastrointestinal dysfunction underlying feed intolerance in the critically ill, as well as the pathophysiology of these dysfunctions, and investigate potential therapeutic measures. While it has been established that enteral nutrition is frequently unsuccessful in the critically ill, assessment of the success of feeding in an Australian intensive care unit (ICU) had not been performed previously. A prospective survey examined the incidence of, and risk factors for, feed intolerance in the ICU at the Royal Adelaide Hospital and demonstrated that, in 40 patients receiving enteral feeding, only about 60% of their nutritional requirements were met at the end of the first week. The main cause for this lack of success was large gastric residual volumes, indicative of delayed gastric emptying (GE). This study, accordingly, quantified the limitations of nutritional delivery in contemporary practice in a local ICU. The results suggest that a better understanding of the pathogenesis underlying this problem is warranted in order to direct research into improved therapies. Scintigraphy is the most accurate technique to measure GE, but is difficult to perform in the ICU. A simpler, more convenient, test would increase the accessibility of GE measurement for both research and clinical purposes. A study comparing a breath test technique and gastric residual volume measurement to the scintigraphic measurement of GE in 25 mechanically ventilated patients demonstrated that GE measured by a breath test technique closely correlated with that measured by scintigraphy. While the breath test had a specificity of 100% it only had a sensitivity of about 60% in the prediction of delayed GE. Similarly, gastric residual volume measurement correlated with scintigraphic measurement of GE but also lacked sensitivity. The breath test has previously been demonstrated to be highly reproducible and it represents a useful option for repeated measurement of GE in the same patient. It is therefore likely to be useful to determine changes in GE over time or in response to a therapeutic intervention. There is a lack of information about the prevalence and determinants of delayed GE in the critically ill. Previous studies have substantial limitations and scintigraphic measurement of GE has only rarely been used. A study comparing GE measured by scintigraphy in 25 patients to 14 healthy subjects demonstrated that GE was delayed in approximately 50% of the ICU patients (>10% retention at 4h) and markedly delayed in about 20% (>50% retention at 4h). Patients with trauma and sepsis appeared to have a relatively higher prevalence of delayed GE (80% and 75% respectively). In addition, the longer the patient had been in ICU the more normal the rate of GE. Quantification of delayed GE may prove useful by defining patients who may benefit from preventative or therapeutic options. The abnormalities in gastrointestinal motility underlying delayed GE in the critically ill are poorly characterised. Simultaneous manometric and gastric emptying measurements were performed in 15 mechanically ventilated patients and 10 healthy subjects. These studies demonstrated that delayed GE was associated with reduced antral activity, increased pyloric activity and increased retrograde duodenal activity in the patients. Persistent fasting motility during feeding was also frequently observed. Furthermore, the feedback response to small intestinal nutrients was enhanced. This latter observation may provide an explanation for the delayed GE and warrants further investigation. Recent studies suggest that the hormone cholecystokinin may be a mediator of increased small intestinal feedback and, if confirmed, this has clear therapeutic implications. Nutrient absorption has rarely been measured in the critically ill. GE and glucose absorption (using 3-O-methyl glucose) were measured simultaneously in 19 ICU patients and compared to 19 healthy subjects. Glucose absorption was shown to be markedly reduced in the patients. Slow GE was associated with delayed, and reduced, absorption. However, glucose absorption was also reduced in patients with normal GE suggesting that reduced glucose absorption in critical illness is only partly due to delayed GE. Accordingly, measures to improve the effectiveness of GE and thereby improve overall nutritional status may be compromised by abnormal small intestinal absorption. The mechanisms underlying this warrant further investigation. A number of therapeutic options directed at improving the delivery of nutrition were examined. In a study involving 20 mechanically ventilated patients, administration of 200mg erythromycin intravenously was shown to be superior to placebo for treating feed intolerance. The optimal dose of erythromycin, however, was unclear. In a subsequent study involving 35 ICU patients, GE was measured using a breath test technique, before and after 2 different doses of erythromycin or placebo and a ‘low’ intravenous dose (70mg) of erythromycin appeared to be as effective as a ‘moderate’ dose (200mg). Both doses were only effective in subjects who had delayed GE at baseline. Based on the outcome of these studies, low doses of erythromycin have subsequently been routinely used to treat feed intolerance in the critically ill patients at the Royal Adelaide Hospital. Animal and human studies suggested that the antibiotic, cefazolin, may have a prokinetic effect. Cefazolin, however, did not demonstrate similar prokinetic activity at a ‘low’ dose (50mg) in a critically ill cohort. The results of this study do not support the use of this agent, at this dose, as a prokinetic, in this population. If nasogastric administration of nutrition proves unsuccessful an alternative is to infuse nutrient directly into the small intestine. However, the placement of feeding tubes distal to the pylorus is technically difficult. A novel technique for postpyloric tube insertion was examined with promising results. In summary, the studies described in this thesis have provided a number of insights relevant to the management of the critically ill by quantifying the prevalence of feed intolerance and delayed GE, characterising some of the disturbances in gastrointestinal motility underlying this problem, and evaluating a number of therapeutic interventions.
http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1345143
Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2008

Inadequate delivery of nutrition to the critically ill is common, and may adversely affect clinical outcomes, including survival. This thesis reports studies designed to characterise the gastrointestinal dysfunction underlying feed intolerance in the critically ill, as well as the pathophysiology of these dysfunctions, and investigate potential therapeutic measures. While it has been established that enteral nutrition is frequently unsuccessful in the critically ill, assessment of the success of feeding in an Australian intensive care unit (ICU) had not been performed previously. A prospective survey examined the incidence of, and risk factors for, feed intolerance in the ICU at the Royal Adelaide Hospital and demonstrated that, in 40 patients receiving enteral feeding, only about 60% of their nutritional requirements were met at the end of the first week. The main cause for this lack of success was large gastric residual volumes, indicative of delayed gastric emptying (GE). This study, accordingly, quantified the limitations of nutritional delivery in contemporary practice in a local ICU. The results suggest that a better understanding of the pathogenesis underlying this problem is warranted in order to direct research into improved therapies. Scintigraphy is the most accurate technique to measure GE, but is difficult to perform in the ICU. A simpler, more convenient, test would increase the accessibility of GE measurement for both research and clinical purposes. A study comparing a breath test technique and gastric residual volume measurement to the scintigraphic measurement of GE in 25 mechanically ventilated patients demonstrated that GE measured by a breath test technique closely correlated with that measured by scintigraphy. While the breath test had a specificity of 100% it only had a sensitivity of about 60% in the prediction of delayed GE. Similarly, gastric residual volume measurement correlated with scintigraphic measurement of GE but also lacked sensitivity. The breath test has previously been demonstrated to be highly reproducible and it represents a useful option for repeated measurement of GE in the same patient. It is therefore likely to be useful to determine changes in GE over time or in response to a therapeutic intervention. There is a lack of information about the prevalence and determinants of delayed GE in the critically ill. Previous studies have substantial limitations and scintigraphic measurement of GE has only rarely been used. A study comparing GE measured by scintigraphy in 25 patients to 14 healthy subjects demonstrated that GE was delayed in approximately 50% of the ICU patients (>10% retention at 4h) and markedly delayed in about 20% (>50% retention at 4h). Patients with trauma and sepsis appeared to have a relatively higher prevalence of delayed GE (80% and 75% respectively). In addition, the longer the patient had been in ICU the more normal the rate of GE. Quantification of delayed GE may prove useful by defining patients who may benefit from preventative or therapeutic options. The abnormalities in gastrointestinal motility underlying delayed GE in the critically ill are poorly characterised. Simultaneous manometric and gastric emptying measurements were performed in 15 mechanically ventilated patients and 10 healthy subjects. These studies demonstrated that delayed GE was associated with reduced antral activity, increased pyloric activity and increased retrograde duodenal activity in the patients. Persistent fasting motility during feeding was also frequently observed. Furthermore, the feedback response to small intestinal nutrients was enhanced. This latter observation may provide an explanation for the delayed GE and warrants further investigation. Recent studies suggest that the hormone cholecystokinin may be a mediator of increased small intestinal feedback and, if confirmed, this has clear therapeutic implications. Nutrient absorption has rarely been measured in the critically ill. GE and glucose absorption (using 3-O-methyl glucose) were measured simultaneously in 19 ICU patients and compared to 19 healthy subjects. Glucose absorption was shown to be markedly reduced in the patients. Slow GE was associated with delayed, and reduced, absorption. However, glucose absorption was also reduced in patients with normal GE suggesting that reduced glucose absorption in critical illness is only partly due to delayed GE. Accordingly, measures to improve the effectiveness of GE and thereby improve overall nutritional status may be compromised by abnormal small intestinal absorption. The mechanisms underlying this warrant further investigation. A number of therapeutic options directed at improving the delivery of nutrition were examined. In a study involving 20 mechanically ventilated patients, administration of 200mg erythromycin intravenously was shown to be superior to placebo for treating feed intolerance. The optimal dose of erythromycin, however, was unclear. In a subsequent study involving 35 ICU patients, GE was measured using a breath test technique, before and after 2 different doses of erythromycin or placebo and a ‘low’ intravenous dose (70mg) of erythromycin appeared to be as effective as a ‘moderate’ dose (200mg). Both doses were only effective in subjects who had delayed GE at baseline. Based on the outcome of these studies, low doses of erythromycin have subsequently been routinely used to treat feed intolerance in the critically ill patients at the Royal Adelaide Hospital. Animal and human studies suggested that the antibiotic, cefazolin, may have a prokinetic effect. Cefazolin, however, did not demonstrate similar prokinetic activity at a ‘low’ dose (50mg) in a critically ill cohort. The results of this study do not support the use of this agent, at this dose, as a prokinetic, in this population. If nasogastric administration of nutrition proves unsuccessful an alternative is to infuse nutrient directly into the small intestine. However, the placement of feeding tubes distal to the pylorus is technically difficult. A novel technique for postpyloric tube insertion was examined with promising results. In summary, the studies described in this thesis have provided a number of insights relevant to the management of the critically ill by quantifying the prevalence of feed intolerance and delayed GE, characterising some of the disturbances in gastrointestinal motility underlying this problem, and evaluating a number of therapeutic interventions.
Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2008

Errata and addenda attached. Bibliography: leaves 195-211. This thesis is concerned with the biology of Eriosoma lanigerum (WAA) and its parasitoid (Aphelinus mali), the impact of the pest on the crop and the effects of pesticides used routinely in South Australian orchards on both woolly apple aphid and the parasitic wasp. The study identifies current management practices of apple growers in South Australia. Aspects of the biology of WAA and A.mali are examined. Work is also done on the toxicity against WAA and A.mali of insecticides used in the control of codling moth and phytophagous mites. The effects of WAA infestation on the growth of young trees are investigated. The seasonal activity of WAA on mature trees is determined over a two season period.

Diversity analysis of Escherichia coli have routinely utilised isolates obtained by culture of faeces on MacConkey selective media, under the assumption that the diversity identified in faecal isolates are representative of similar diversity in E. coli in the gastrointestinal tract (GIT). This study has addressed this important issue by specifically isolating E. coli from different regions of the gut in pigs and subjecting them to enzymatic multilocus enzyme electrophoresis (MLEE) and molecular virulence factor (VF) analysis to ascertain whether E. coli populations inhabiting different regions of the gut are different from each other. Combination of these results showed that on average, E. coli strains isolated from the upper GIT region (small intestine) of the pig are distinctly different from the E. coli strains isolated from the lower GIT region (large intestine). An important aspect of the finding that faecal E. coli are not truly representative of the diversity in the GIT is the mechanism used by specific clonotypes that have adapted to different geographical habitats to survive challenge from incoming strains.
Doctor of Philosophy (PhD)

Wang, Hui Chuan.
Thesis (Ph.D.)--Chinese University of Hong Kong, 2013.
Includes bibliographical references (leaves 184-202).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Abstract also in Chinese.

Introduction: Gastric cancer (GC) is ranked as the second most common fatal malignancy worldwide. Although Helicobacter pylori is recognized as a major predisposing factor for non-cardia GC, infection alone is not sufficient to cause cancer. This thesis aimed to determine the variation in host genetic polymorphisms in subjects from Malaysia and Singapore and to examine the role of H. pylori infection, host genetic factors and dietary factors in the etiology of non-cardia GC in Chinese subjects resident in Malaysia. Methods: Functional dyspepsia (FD) controls from three ethnic groups in Malaysia, Chinese (123), Indian (110) and Malay (84) and Singaporean Chinese (127) plus Malaysian Chinese gastric cancer cases (55)were examined. Polymorphisms in IL-1B-511, IL-1RN, IL-10 cluster, TNFA-308 and TLR5+1174 were determined by PCR-RFLP or PCR; H. pylori status by serology, dietary intake by questionnaire and gastric IL-1b levels by real time PCR. Results: 1) Significant differences existed in the frequency of all polymorphisms, except IL-1B-1473 and TNFA-308, in the three Malaysian ethnic groups and in the IL-1B-511 polymorphism in Malaysian and Singaporean Chinese FD 2) Globally, two distinct patterns of IL-1B-511, IL-1RN, IL-10-1082, IL-10-592 and TNFA-308 exist, Western and East-Asian 3) In Malaysian Malays, the IL-10 ATA haplotype was associated with H. pylori susceptibility 4) In Malaysian Chinese an increased risk of GC was associated with carriage of the IL-1B-1473 G allele {OR=4.4(1.3-15.3)} and the IL-1B-511 C allele {OR=1.8(0.8-4.1)} 5) Increased levels of IL-1b were observed in Singaporean and Malaysian Chinese FD subjects carrying the IL-1-511C and IL-1-1473G alleles 6) Malaysian Chinese not consuming fresh fruit and vegetables had the highest risk of GC {OR=10.2 (3.4-30.6)} 7) The highest risk of GC {OR=37.3(3.3-424.8)} was observed in H. pylori positive Malaysian Chinese who carried both the IL-1B-511C and IL-1B-1473G alleles and did not consume fresh fruit and vegetables. Conclusions: In Malaysian Chinese, H. pylori infection, host genetic and dietary factors all contribute to the risk of GC. However the significant difference observed in the frequency of host genetic polymorphisms within and between ethnic groups suggests that a single group of risk factors cannot be used to determine GC risk across all populations.

Includes bibliographical references.
59 leaves :
Title page, contents and abstract only. The complete thesis in print form is available from the University Library.
Various articles published by John Robin Warren on the discovery and pathology of Helicobacter pylori.
Thesis (M.D.)--University of Adelaide, Dept. of Medicine, 2000

H. pylori is one of the most significant discoveries in gastroenterology in the past century. It is associated with a wide range of gastroduodenal pathologies and gastric cancer. Antibiotic resistance in H. pylori has emerged as a significant clinical problem. The body of work contained within this dissertation was carried out to investigate an alternative therapy based on observations of the traditional therapy for gastric disease in the Middle East. One of these traditional therapies centres on plants belonging to the Pistacia genus. This study represents the first reported investigation into the composition and biological activity of the trunk bark exudates of Pistacia atlantica Kurdic (P. a. Kurdica), Pistacia atlantica Mutica (P. a. Mutica) and Pistacia atlantica Cabolica (P. a. Cabolica), resinous gums that have been termed here ‘Kurdica Gum’, ‘Mutica Gum ’ and ‘Cabolica Gum ’ respectively. The antimicrobial screening of the trunk exudates of the genus Pistacia led to the characterization of the most active fraction of the Kurdica gum. This fraction was subsequently subjected to sub-fractionation leading to the discovery of fundamentally new information that went beyond H. pylori, expanding the original parameters of the project. The extent of these findings suggests that new classes of antibiotics might have been discovered. Primary studies on their structure and potential mechanism of action has been undertaken. Thirteen novel antimicrobial agents were identified. Based on the characteristics of these isolated fractions, 50 new compounds were modelled; of which 30 hypothetically have an MIC consistent with contemporary antibiotics and could represent viable lead compounds for commercial development.
Doctor of Philosophy

蠕動是一種能夠幫助食物通過胃腸道以及促進胃腸道產生能動性的類似波浪的收縮運動。它由一種叫做Cajal (ICC)間質細胞的起搏器細胞產生的慢波所控制。ICCs亦幫助由腸神經系統(ENS)到平滑肌的信息傳導。嚙齒動物和人類實驗表明，老化所導致的ICC細胞數量下降和腸神經退化與排便睏難和便秘有關。通過研究ICC和ENS在正常老化情況下和加速膽碱能神經元喪失的阿爾茲海默症(AD)老鼠模型(Tg2576)中的變化，我們對治療神經退化性疾病也許會有新的認識。本課題的目的在于，研究老化情況下正常老鼠模型及澱粉樣前體蛋白質(APP)過量表達下的AD老鼠模型的胃腸道在形態及功能上的變化。
六個月大的Tg2576和同齡野生型對照的全樣載片免疫組化實驗顯示， 十二指腸 (P < 0.05)和迴腸 (P < 0.01)中的腸神經細胞顯著降低，迴腸 (P < 0.001)中的GFAP陽性的腸神經膠質細胞也顯著消失。S100陽性的腸神經膠質細胞在胃竇（胃部中的起搏區域）(P < 0.05), 迴腸 (P < 0.05)和結腸 (P < 0.05)中顯著喪失。這些結果表明，在早期的AD階段，ENS已經出現變質。ICC細胞數量在六個月大的Tg2576和同齡野生型對照的所有腸胃部分並沒有顯著性差異 (P > 0.05)。同時，早期AD階段的基本蠕動節奏也並沒有發生改變。除此之外，結腸和十二指腸的GFAP/S100陽性的腸神經膠質細胞比例並沒有顯著增加，表明在早期AD階段，可能出現了炎症。
利用石蠟切片進行β澱粉樣蛋白免疫組化，天狼猩紅溶液化驗和硫代黃素T溶液化驗可以測試不溶的澱粉樣斑塊是否存在。結果指出在六個月大的Tg2576所有腸胃部分都觀察到澱粉樣斑塊聚集而在不同的腸胃部分聚集的程度都有所分別。除了結腸外，六個月大的野生型對照所有腸胃部分都觀察不到澱粉樣斑塊聚集。澱粉樣斑塊形成的增長可能和早期AD階段出現的腸神經細胞和腸神經膠質細胞喪失互相關聯。
應用電泳轉移酶標免疫印斑技術，測試六個月大的Tg2576和同齡野生型對照的迴腸和結腸中，膽碱乙酰轉移酶 (ChAT，出自興奮神經元)， 神經元型一氧化氮合酶(nNOS，出自抑制神經元)， 膠質細胞源性神經營養因子 (GDNF， 出自腸神經膠質細胞)和可溶解的β澱粉樣蛋白寡聚體的表達是否改變。和野生型對照相比，Tg2576的nNOS的表達在迴腸 (P < 0.05) 而不是結腸 (P > 0.05) 中顯著增加。而ChAT，GDNF和各β澱粉樣蛋白寡聚體 (十二聚物，九聚物和六聚物)在六個月大的Tg2576和同齡野生型對照之間並沒有顯著改變 (P > 0.05)。綜上結果表明，在早期AD階段，腸胃道中的抑制信號有所增加，但是β澱粉樣蛋白寡聚體可能不是引致腸胃道中的腸神經細胞和腸神經膠質細胞喪失的原因。
在腸胃道的組織學和生化實驗之後，我們利用了微電極陣列 (MEA) 系統來量度出自胃竇和迴腸的慢波信號。量度出來的主導頻率(DF)和功率分佈可以成為測量在老化的ICR老鼠和早期AD階段下腸胃道的功能有沒有變化的參數。在硝苯地平存在下，尼古丁顯著地刺激三個月大 (P < 0.05) 和 六個月大 (P < 0.05) 的ICR老鼠中胃竇和迴腸的慢波活動但未能引起十二個月大 (P > 0.05) 的ICR老鼠中的慢波活動，說明神經退化可能在十二個月的年齡開始。附加了河豚毒素的情況下，尼古丁不能再刺激三個年齡組中胃竇和迴腸的慢波活動 (P > 0.05)，由此證明了尼古丁是對腸神經細胞起作用再去激發ICC的活動。六個月大的Tg2576和同齡野生型對照之間的胃竇和迴腸的基准讀數沒有顯著分別 (P > 0.05)。然而，尼古丁顯著地增加野生型對照中胃竇和迴腸的DF和胃電過速範圍 (P < 0.05) 但是不能刺激Tg2576中胃竇和迴腸的電流活動 (P > 0.05)，示意在早期AD階段腸胃道中已經出現了腸神經細胞和/或腸神經膠質細胞喪失。
綜上所言，研究結果提出AD老鼠模型有形態學，生物化學和功能上的轉變。本課題提供了在研究神經退化疾病上的基礎，也支持ENS是中樞神經系統早期病變前的關口這個假設。
Peristalsis is the wave-like contraction that moves food along the gastrointestinal (GI) tract and generates GI motility. Peristalsis is modulated by slow waves that originate from pacemaker cells called interstitial cell of Cajal (ICC). ICCs also modulate and transduce inputs from the enteric nervous system (ENS) to the smooth muscle. Recent studies in rodents and humans demonstrated that a decrease in ICC number and enteric neurodegeneration during ageing is associated with difficult bowel movements and constipation. By studying ICC and the ENS during normal aging and in a mouse model (Tg2576) of Alzheimer’s disease (AD) where cholinergic loss may be exaggerated, we may gain new perspectives on the treatment of degenerative diseases. The aim of the present study therefore, was to investigate the morphological and functional changes of the GI tract of mice during ageing and in an AD mouse model over-expressing amyloid precursor protein (APP) using an isolated tissue approach.
Whole mount immunohistochemistry of 6-month-old Tg2576 mice and their age-matched wild type (WT) controls revealed that there were significant losses of enteric neurons in the duodenum (P < 0.05) and ileum (P < 0.001), and of GFAP-positive enteric glial cells in the ileum (P < 0.001). There was also a loss of S100-positive glial cells in the antrum (pacemaker region in the stomach) (P < 0.05), ileum (P < 0.05) and colon (P < 0.05). These results indicated the alteration of the ENS during the early stages of AD. There were no differences in ICC arears of all GI regions between 6-month-old Tg2576 mice and their age-matched WT controls (P > 0.05), and there was no alteration of basal peristaltic rhythm during the early stages of AD. The non-significant increase of GFAP to S100 enteric glial cell ratio in the duodenum and colon might indicate an ongoing inflammatory process in these two GI regions during the early stages of AD.
The presence of insoluble amyloid plaques was studied using Aβ immunohistochemistry, Sirius red assay and Thioflavin-T assay on paraffin wax sections. The aggregation of amyloid plaques was observed in all the GI regions of 6-month-old Tg2576 mice and the levels of amyloid plaque varied in different regions. No amyloid plaques were found in the GI tract of 6-month-old WT animals excepting the colon. The increase in formation of amyloid plaques might be correlated to the losses of enteric neurons and enteric glial cells during the early stages of AD.
Western blot analysis was performed on frozen sections of tissues from the ileum and colon to investigate whether there were changes in choline acetyltransferase (ChAT, from excitatory neurons), neuronal nitric oxide synthase (nNOS, from inhibitory neurons), glial cell line-derived neurotrophic factor (GDNF, from enteric glia) and soluble Aβ oligomers between 6-month-old Tg2576 mice and WT controls. nNOS expression significantly increased in the ileum (P < 0.05) but not in the colon (P > 0.05) of Tg2576 mice compared with WT controls. There were no differences in the expressions of ChAT, GDNF and Aβ oligomers (docecamer, nonamer and hexamer) in the ileum and colon between Tg2576 mice and WT controls (P > 0.05). These results imply that there is an increase in the inhibitory signal in the GI tract during the early stages of AD but soluble Aβ oligomers might not be the cause of neuronal and glial losses in the GI tract.
Following histological and biochemical studies of different GI regions, slow wave signals from the antrum and ileum were measured using a microelectrode array (MEA) system. The dominant frequencies (DFs) and power distributions were measured and these served as parameters for measuring functional changes in the GI tract during ageing in ICR mice and the early stages of AD. In the presence of nifedipine, nicotine significantly stimulated the slow wave activities in the antrum and ileum of 3-month-old (P < 0.05) and 6-month-old (P < 0.05) ICR mice but failed to trigger the slow wave activities in 12-month-old (P > 0.05) ICR mice, suggesting the neurodegeneration might begin with the age between 6 and 12 months. With the addition of tetrodotoxin, nicotine failed to stimulate the slow wave activities in the antrum and ileum of three age groups (P > 0.05) and it showed that nicotine only acted on enteric neurons to trigger the ICC activities. There were no differences in the antral and ileal baseline recordings between 6-month-old Tg2576 mice and their age-matched WT controls (P > 0.05). However, nicotine significantly increased DFs and tachygastria ranges of the antrum and ileum in WT controls (P < 0.05) but failed to increase electrical activitiy of the antrum and ileum in Tg2576 mice (P > 0.05), thus suggesting a loss of neuronal and/or glial cells in the GI tract during the early stages of AD.
In conclusions, these findings suggest the mouse model for AD has morphological, biochemical and functional changes in the GI tract. The present studies provide a foundation for the investigation of degenerative diseases and support the hypothesis that the ENS may be the gateway for the early pathological changes in the central nervous system.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Hui, Chin Wai.
Thesis (M.Phil.)--Chinese University of Hong Kong, 2012.
Includes bibliographical references (leaves 180-200).
Abstracts also in Chinese.
PUBLICATIONS RELATED TO THE WORK IN THIS THESIS --- p.i
ABSTRACT --- p.ii
摘要 --- p.iv
ACKNOWLEDGEMENTS --- p.vi
LIST OF ABBREVIATIONS --- p.vii
Chapter CHAPTER 1 --- Introduction --- p.1
Chapter 1.1 --- General introduction --- p.1
Chapter 1.2 --- Interstitial cells of Cajal (ICCs) as electrical pacemaker cells in GI tract --- p.1
Chapter 1.2.1 --- ICC subtypes in GI tract --- p.2
Chapter 1.3 --- Hypotheses of slow wave generation --- p.4
Chapter 1.3.1 --- Mechanisms of the NSCC pacemaking hypothesis --- p.5
Chapter 1.3.2 --- Mechanisms of the alternative hypothesis --- p.6
Chapter 1.4 --- Involvement of ion channels in slow wave generation of ICC --- p.6
Chapter 1.4.1 --- Calcium channels --- p.6
Chapter 1.4.2 --- Sodium channels --- p.7
Chapter 1.4.3 --- Potassium channels --- p.7
Chapter 1.4.4 --- Chloride channels --- p.8
Chapter 1.4.5 --- Non-selective cation channels --- p.8
Chapter 1.5 --- Distribution of several types of receptors in ICC --- p.11
Chapter 1.5.1 --- Purinergic receptors --- p.11
Chapter 1.5.2 --- Muscarinic receptors --- p.11
Chapter 1.5.3 --- Tachykinin receptors --- p.12
Chapter 1.5.4 --- Vasoactive intestinal peptide receptors --- p.12
Chapter 1.5.5 --- Serotonin receptors --- p.13
Chapter 1.6 --- Introductions and functions of enteric nervous system --- p.15
Chapter 1.6.1 --- Interaction amongst the central, peripheral and enteric nervous system: brain-gut axis --- p.15
Chapter 1.6.2 --- Enteric neuronal subtypes in the GI tract --- p.15
Chapter 1.6.2.1 --- Motor neurons --- p.16
Chapter 1.6.2.2 --- Interneurons --- p.16
Chapter 1.6.2.3 --- Intrinsic primary afferent neurons --- p.18
Chapter 1.6.3 --- Enteric glial cells --- p.18
Chapter 1.6.3.1 --- Enteric glial subtypes in the GI tract --- p.18
Chapter 1.6.3.2 --- Communication between enteric neurons and glial cells --- p.19
Chapter 1.6.3.3 --- Possible functions of enteric glial cells in the GI tract --- p.19
Chapter 1.6.3.3.1 --- Secretion of neurotrophic factors --- p.20
Chapter 1.6.3.3.2 --- Secretion of reduced glutathione --- p.20
Chapter 1.6.3.3.3 --- Secretion of transforming growth factor-beta 1 --- p.21
Chapter 1.7 --- Interactions amongst ICC, enteric neurons and enteric glial cells --- p.21
Chapter 1.8 --- Gastrointestinal disorders --- p.22
Chapter 1.8.1 --- Mechanisms for cell depletion --- p.22
Chapter 1.8.1.1 --- Autoimmune attack --- p.22
Chapter 1.8.1.2 --- Hyperglycaemia and diabetes mellitus --- p.24
Chapter 1.8.1.3 --- Oxidative stress --- p.25
Chapter 1.8.1.4 --- Ageing --- p.26
Chapter 1.9 --- Alzheimer’s disease --- p.28
Chapter 1.9.1 --- Genetics and pathogenesis of Alzheimer’s disease --- p.28
Chapter 1.9.1.1 --- Aggregation of amyloid beta protein --- p.29
Chapter 1.9.1.2 --- Genetic factors of AD --- p.29
Chapter 1.9.1.3 --- Tau hyperphosphorylation and neurofibrillary tangles --- p.31
Chapter 1.9.2 --- Current treatment for Alzheimer’s disease --- p.33
Chapter 1.9.2.1 --- Symptomatic treatment --- p.33
Chapter 1.9.2.2 --- Disease-modifying treatment --- p.34
Chapter 1.9.2.3 --- Other potential drugs for AD treatment --- p.35
Chapter 1.9.3 --- Possible animal models for AD investigation --- p.36
Chapter 1.9.4 --- Possible correlations between Alzheimer’s disease and the enteric nervous system --- p.36
Chapter 1.10 --- Aim of study --- p.37
Chapter CHAPTER 2 --- Investigation into the morphologies of enteric nervous system and interstitial cell of Cajal in Tg2576 mice --- p.38
Chapter 2.1 --- Introduction --- p.38
Chapter 2.1.1 --- Molecular markers for ICC, ENC, and EGC --- p.38
Chapter 2.1.2 --- Aims and objectives --- p.39
Chapter 2.2 --- Materials and methods --- p.41
Chapter 2.2.1 --- Animals --- p.41
Chapter 2.2.2 --- Tissue preparation --- p.41
Chapter 2.2.3 --- Immunohistochemistry --- p.42
Chapter 2.2.4 --- Image acquisition and analysis --- p.43
Chapter 2.3 --- Results --- p.44
Chapter 2.3.1 --- General observations --- p.44
Chapter 2.3.2 --- Area and pattern of ICCs and the ENS in the stomach --- p.46
Chapter 2.3.3 --- Area and pattern of ICCs and the ENS in the duodenum --- p.52
Chapter 2.3.4 --- Area and pattern of ICCs and the ENS in the jejunum --- p.56
Chapter 2.3.5 --- Area and pattern of ICCs and the ENS in the ileum --- p.60
Chapter 2.3.6 --- Area and pattern of ICCs and the ENS in the colon --- p.66
Chapter 2.4 --- Discussion --- p.70
Chapter 2.4.1 --- Major findings --- p.70
Chapter 2.4.2 --- Possible alterations of the ENS during AD --- p.70
Chapter 2.4.3 --- Morphological changes of the ENS in relation to genotype --- p.71
Chapter 2.4.4 --- Morphological changes of ICCs in relation to genotype --- p.72
Chapter 2.4.5 --- Morphological changes of the ENS and ICCs in relation to GI regions --- p.72
Chapter 2.4.6 --- Inflammatory conditions in different GI regions --- p.73
Chapter 2.5 --- Conclusion --- p.74
Chapter CHAPTER 3 --- Formation of amyloid plaques in the brain and the GI tract of Tg2576 mice --- p.75
Chapter 3.1 --- Introduction --- p.75
Chapter 3.1.1 --- The absence of amyloid plaques in rodents --- p.75
Chapter 3.1.2 --- Overexpression of human APP in transgenic mice --- p.76
Chapter 3.1.3 --- Distribution of human APP and Aβ deposition in human and transgenic mice --- p.77
Chapter 3.1.4 --- Transgene and promoter in Tg2576 mouse --- p.77
Chapter 3.1.5 --- Methods for Aβ plaque detection --- p.78
Chapter 3.1.6 --- Aim and objectives --- p.78
Chapter 3.2 --- Materials and methods --- p.80
Chapter 3.2.1 --- Animals --- p.80
Chapter 3.2.2 --- Tissue processing --- p.80
Chapter 3.2.3 --- Preparation of paraffin wax blocks and slide sections --- p.81
Chapter 3.2.4 --- Aβ immunohistochemistry --- p.82
Chapter 3.2.5 --- Sirius red assay --- p.83
Chapter 3.2.6 --- Thioflavin-T assay --- p.84
Chapter 3.2.7 --- Image acquisition --- p.84
Chapter 3.3 --- Results --- p.85
Chapter 3.3.1 --- Aβ immunohistochemistry --- p.85
Chapter 3.3.1.1 --- The absence of positive immunoreactivity in the brain --- p.85
Chapter 3.3.1.2 --- The presence of positive immunoreactivity in the GI tract of Tg2576 mice --- p.85
Chapter 3.3.2 --- Sirius red assay --- p.92
Chapter 3.3.2.1 --- The presence of positive immunoreactivity in the brain of Tg2576 mice --- p.92
Chapter 3.3.2.2 --- Characteristics of Sirius red staining in the GI tract --- p.92
Chapter 3.3.2.3 --- The presence of positive immunoreactivity in the GI tract of Tg2576 mice --- p.92
Chapter 3.3.3 --- Thioflavin-T assay --- p.98
Chapter 3.3.3.1 --- The presence of positive immunoreactivity in the brain of Tg2576 mice --- p.98
Chapter 3.3.3.2 --- The presence of positive immunoreactivity in the GI tract of Tg2576 mice --- p.98
Chapter 3.4 --- Discussion --- p.104
Chapter 3.4.1 --- The presence of a small amount of amyloid plaques in the brain of young Tg2576 mice --- p.104
Chapter 3.4.2 --- The presence of amyloid plaques in the GI tract --- p.104
Chapter 3.4.3 --- Plaque formation in relation to genotype --- p.105
Chapter 3.4.4 --- Possible effects of amyloid plaques in the brain and GI tract --- p.106
Chapter 3.5 --- Conclusion --- p.108
Chapter CHAPTER 4 --- Expression of Aβ oligomers, ChAT, nNOS and GDNF in the GI tract of Tg2576 mice --- p.109
Chapter 4.1 --- Introduction --- p.109
Chapter 4.1.1 --- Common and peripheral types of ChAT --- p.109
Chapter 4.1.2 --- Three subtypes of NOS --- p.111
Chapter 4.1.3 --- Functions of glial cell line-derived neurotrophic factor in the ENS --- p.112
Chapter 4.1.4 --- Neurotoxicity of soluble Aβ peptides --- p.113
Chapter 4.1.5 --- Aims and objectives --- p.113
Chapter 4.2 --- Materials and methods --- p.115
Chapter 4.2.1 --- Animals --- p.115
Chapter 4.2.2 --- Preparation of materials --- p.115
Chapter 4.2.3 --- Sample preparation --- p.117
Chapter 4.2.4 --- Separating and stacking gels preparation --- p.118
Chapter 4.2.5 --- Western blot --- p.119
Chapter 4.2.6 --- Image acquisition and analysis --- p.120
Chapter 4.3 --- Results --- p.122
Chapter 4.3.1 --- Increase in nNOS expression in the ileum of Tg2576 mice --- p.122
Chapter 4.3.2 --- No changes in the expressions of Aβ oligomers, ChAT, nNOS and GDNF in the colon of Tg2576 mice --- p.122
Chapter 4.4 --- Discussion --- p.127
Chapter 4.4.1 --- The absence of “cholinergic hypothesis of AD in the GI tract of Tg2576 mice --- p.127
Chapter 4.4.2 --- Increased expression of nNOS in the ileum of Tg2576 mice --- p.128
Chapter 4.4.3 --- Neuronal and glial losses may be related to the reduced GDNF expression --- p.129
Chapter 4.4.4 --- No relationship between the Aβ oligomers and neuronal damages in the GI tract --- p.129
Chapter 4.5 --- Conclusion --- p.129
Chapter CHAPTER 5 --- Microelectrode array (MEA) study on slow wave activity in the GI tract --- p.131
Chapter 5.1 --- Introduction --- p.131
Chapter 5.1.1 --- Components in peristalsis-controlling unit --- p.131
Chapter 5.1.2 --- Techniques in evaluating slow wave activity --- p.131
Chapter 5.1.2.1 --- Patch clamp --- p.132
Chapter 5.1.2.2 --- Calcium imaging --- p.132
Chapter 5.1.3 --- Application of microelectrode array in evaluating slow wave activity --- p.134
Chapter 5.1.4 --- Aims and objectives --- p.136
Chapter 5.2 --- Methods and materials --- p.137
Chapter 5.2.1 --- Animals --- p.137
Chapter 5.2.2 --- Tissue preparation --- p.137
Chapter 5.2.3 --- Electrical recordings --- p.138
Chapter 5.2.4 --- Analysis and Statistics --- p.139
Chapter 5.3 --- Results --- p.142
Chapter 5.3.1 --- Experiments on ICR mice --- p.142
Chapter 5.3.1.1 --- Nicotine stimulates the slow wave activity in the antrum in the presence of NIF but not in the presence of NIF and 500 nM TTX --- p.142
Chapter 5.3.1.2 --- Nicotine stimulates the slow wave activity in the ileum in the presence of NIF but only partially stimulates activity in the presence of NIF and 500 nM TTX --- p.152
Chapter 5.3.1.3 --- The use of 1 μM TTX completely blocked the nicotine stimulation in the ileum --- p.160
Chapter 5.3.1.4 --- The dominant frequency of baseline increased in the ileum of 12-month-old ICR but not in the antrum in the presence of NIF --- p.162
Chapter 5.3.2 --- Experiments on Tg2576 mice and their wild type controls --- p.164
Chapter 5.3.2.1 --- No differences in both antral and ileal baseline DFs between 6- month-old non-transgenic and Tg2576 mice --- p.164
Chapter 5.3.2.2 --- Nicotine stimulates slow wave activity in the antrum of 6-month-old wild type controls but not of Tg2576 mice --- p.164
Chapter 5.3.2.3 --- Nicotine stimulates slow wave activity in the ileum of 6-month-old wild type controls but not of Tg2576 mice --- p.167
Chapter 5.4 --- Discussion --- p.171
Chapter 5.4.1 --- Pharmacological effects of nicotine in the GI tract --- p.171
Chapter 5.4.2 --- Excitatory effects of nicotine in the slow wave activities of the stomach and ileum --- p.172
Chapter 5.4.3 --- Changes of ICC functions and neuronal activities during ageing --- p.174
Chapter 5.4.4 --- Enteric neurodegeneration leads to alteration in the ENS function in Tg2576 mice --- p.175
Chapter 5.4.5 --- Conclusion --- p.176
Chapter CHAPTER 6 --- Concluding discussion --- p.177
REFERENCES --- p.180

無線膠囊內窺鏡（CE）是一種用於檢查整個胃腸道，尤其是小腸的無創技術。它極大地改善了許多小腸疾病的診斷和管理方式，如不明原因的消化道出血，克羅恩病，小腸腫瘤，息肉綜合征等。儘管膠囊內窺鏡有很好的臨床表現，但它仍然有一定的局限性。主要問題是每次檢查產生約50,000 幅低質量的圖像，對於醫生來說，評估如此大量的圖像是一項非常耗時、耗力的工作。
到目前為止，對於膠囊內窺鏡的分析和評估，學者們都把膠囊內窺鏡圖像視為單獨的，獨立的觀測對象。事實並非如此，因為圖像之間往往有顯著的重疊。特別是當膠囊內窺鏡在被小腸蠕動緩緩推動時，它可以捕捉同一病灶的多個視圖。我們的研究目的是使用所有可用的資訊，包括多幅圖像，研究對於膠囊內窺鏡的電腦輔助診斷（CAD）系統。
在這篇論文中，我們提出了一個嵌入分類器的多類隱馬爾可夫模型（HMM）的方案，它可以融合多幅相鄰圖像的時間資訊。由於膠囊內窺鏡圖像的品質比較低，我們首先進行預處理，以加強膠囊內窺鏡圖像，增加其對比度，消除噪聲。我們調查研究了多種圖像增強的方法，並調整了它們的參數使其適用於膠囊內窺鏡圖像。
對於基於單幅圖像的有監督的分類，AdaBoost 作為一個集成分類器來融合多個分類器，即本論文中的支持向量機（SVM），k-近鄰（k-NN），貝葉斯分類。在分類之前，我們提取和融合了顏色，邊緣和紋理特徵。
對於無線膠囊內窺鏡的視頻摘要，我們提出了有監督和無監督的兩類方法。對於有監督方法，我們提出了一個基於隱馬爾可夫模型的，靈活的，可擴展的框架，用於整合膠囊內窺鏡中連續圖像的時間資訊。它可以擴展到多類別，多特徵，多狀態。我們還提出了聯合隱馬爾可夫模型和並行隱馬爾可夫（PHMM）模型對系統進行改進，它們可以被看作是決策級的資訊融合。聯合隱馬爾可夫模型通過多層次的隱馬爾可夫模型，結合不同的資訊來源，對膠囊內窺鏡視頻進行分類和視頻摘要。 並行隱馬爾可夫模型採用貝葉斯推理，在決策時融合多個不同來源的資訊。對於無監督的方法，我們首先提出了一種基於顏色的特徵提取方法。在反色顏色空間中對亮度不變的色度不變矩用來表示膠囊內窺鏡圖像的顏色特徵。接著，我們又提出了一種基於輪廓元（Contourlet）變換的局部二元模式（LBP）作為紋理特徵。在特徵空間中，我們測量了相鄰圖像的距離，並把它視為一個位於二維平面上的開放輪廓上的點。 然後，我們採用一個無參數的關鍵點檢測方法檢測在視頻片段上的突變關鍵點。基於這些突變關鍵點，我們對膠囊內窺鏡視頻進行分割。最後，在每段被分割的視頻片段上，我們通過提取有代表性的關鍵幀來實現膠囊內窺鏡視頻摘要。我們分別用模擬和真實的病人數據進行實驗，對提出的方法進行驗證，結果表明了我們所提出的方案的有效性。它在實現自動評估膠囊內窺鏡圖像上具有很大的潛力。
Wireless Capsule Endoscopy (CE) is a non-invasive technology to inspect the whole gastrointestinal (GI) tract, especially the small intestine. It has dramatically changed the way of diagnosis and management of many diseases of the small intestine, such as obscure gastrointestinal bleeding, Crohn’s disease, small bowel tumors, polyposis syndromes, etc. Despite its promising clinical findings, it still has some limitations. The main problem is that it requires manual assessment of approximately 50,000 low quality images per examination which is highly time-consuming and labor-intense.
CE analysis and assessment so far treated CE images as individual and independent observations. It is obviously not the case as there is often significant overlap among images. In particular, CE captures multiple views of the same anatomy as the capsule is slowly propelled by peristalsis. Our broader work aims to perform computer aided diagnosis (CAD) in endoscopy using all available information, including multiple images.
In this dissertation, a framework of multi-class Hidden Markov Models (HMM) embedded with statistical classifiers for combining information from multiple CE images is proposed. Due to the low quality of CE image, pre-processing is performed to enhance CE images by increasing the contrast and removing noises. Several image enhancement methods are investigated and customized for CE images. For frame-based supervised classification, AdaBoost is used as the ensemble classifier to combine multiple classifiers, i.e. support vector machine (SVM), k-nearest neighbor (k-NN), and Bayes classifier. Before classification, color, edge and texture features are extracted and fused. Finally, both supervised and unsupervised methods are proposed for CE study synopsis. For supervised method, a flexible and extensible framework based on HMM is developed to integrate temporal information in CE images. It can be extended to multi-class, multi-features, and multi-states. Improvements can be made by combined HMM and Parallel HMM (PHMM) which are introduced as decision-level fusion schemes. Combined HMM considers different sources via a multi-layer HMM model to perform classification and video synopsis. PHMM employs Bayesian inference to combine the recognition results at decision level. For unsupervised method, illumination-independent opponent color moment invariants and local binary pattern (LBP) based on Contourlet transform are explored as color and texture features, respectively. Pair-wise image dissimilarity is measured in the feature space and treated as points on an open contour in a 2-D plane. CE video is segmented based on sudden change points which are detected using a non-parametric key-point detection method. From each segment, representative frames are extracted to summarize the CE video. Validation results on simulated and real patient data show promising performance of the proposed framework. It has great potential to achieve automatic assessment for CE images.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
Zhao, Qian.
Thesis (Ph.D.)--Chinese University of Hong Kong, 2012.
Includes bibliographical references (leaves 142-175).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Abstract also in Chinese.
Abstract --- p.ii
Acknowledgments --- p.vii
List of Tables --- p.xiii
List of Figures --- p.xv
Chapter 1 --- The Relevance of Synopsis --- p.1
Chapter 1.1 --- Problem Statement --- p.1
Chapter 1.2 --- Application - Capsule Endoscopy Assessment --- p.4
Chapter 1.3 --- Literature Review --- p.9
Chapter 1.3.1 --- Methods Based on Frame Classification --- p.11
Chapter 1.3.2 --- Methods Integrating Temporal Information --- p.14
Chapter 1.4 --- Contributions --- p.19
Chapter 1.5 --- Organization --- p.23
Chapter 2 --- Preliminary --- p.25
Chapter 2.1 --- Hidden Markov Model (HMM) --- p.25
Chapter 2.2 --- Factorial HMM --- p.35
Chapter 3 --- Temporal Integration in Capsule Endoscopy Image Analysis --- p.37
Chapter 3.1 --- Pre-processing --- p.38
Chapter 3.2 --- Feature Extraction --- p.43
Chapter 3.3 --- Frame-based Supervised Classification --- p.47
Chapter 3.3.1 --- Supervised Classification using Individual Frames --- p.47
Chapter 3.3.2 --- Ensemble Learning Based on AdaBoost --- p.50
Chapter 3.4 --- Sequence-based Supervised Classification --- p.52
Chapter 3.5 --- Experiments --- p.58
Chapter 3.5.1 --- Capsule Endoscopy Image Enhancement --- p.60
Chapter 3.5.2 --- Frame-based Supervised Classification --- p.67
Chapter 3.5.3 --- Image Sequence Classification --- p.68
Chapter 3.6 --- Discussion --- p.80
Chapter 3.7 --- Summary --- p.82
Chapter 4 --- Capsule Endoscopy Study Synopsis --- p.98
Chapter 4.1 --- Supervised Synopsis Using Statistical Models --- p.98
Chapter 4.2 --- Unsupervised Synopsis via Representative Frame Extraction --- p.100
Chapter 4.2.1 --- Feature Extraction --- p.100
Chapter 4.2.2 --- Non-parametric Key-point Detection --- p.111
Chapter 4.2.3 --- Representative Frame Extraction --- p.112
Chapter 4.3 --- Experiments --- p.119
Chapter 4.3.1 --- Supervised Synopsis Based on HMM --- p.119
Chapter 4.3.2 --- Unsupervised Synopsis --- p.125
Chapter 4.4 --- Discussion --- p.132
Chapter 4.5 --- Summary --- p.133
Chapter 5 --- Conclusions and Future Work --- p.138
Chapter 5.1 --- Conclusions --- p.138
Chapter 5.2 --- Future Work --- p.141
Bibliography --- p.142

Ho Toi Sze Joyce.
Thesis (M.Phil.)--Chinese University of Hong Kong, 2005.
Includes bibliographical references (leaves 65-74).
Abstracts in English and Chinese.
Acknowledgement --- p.ii
Contents --- p.iii
Abstract --- p.viii
List of Abbreviations --- p.xvii
List of Tables --- p.xix
List of Figures --- p.xx
Chapter Chapter 1 --- Introduction --- p.1
Chapter 1.1 --- The role of Non-steroidal anti-inflammatory drugs (NSAIDs) --- p.1
Chapter 1.2 --- NSAID-induced gastrointestinal (GI) toxicity --- p.1
Chapter 1.2.1 --- Pathogenesis of NSAID-induced GI toxicity --- p.2
Chapter 1.2.2 --- GI symptoms --- p.4
Chapter 1.2.3 --- GI ulcers --- p.4
Chapter 1.2.4 --- GI complications --- p.5
Chapter 1.2.5 --- Risk factor for GI complications --- p.6
Chapter 1.2.6 --- Ulcerogenicity of different NSAIDs in upper GI events --- p.6
Chapter 1.3 --- Prevention of NSAID-induced GI toxicity --- p.7
Chapter 1.3.1 --- H2-receptor antagonists --- p.8
Chapter 1.3.2 --- Misoprostol --- p.8
Chapter 1.3.3 --- Proton Pump Inhibitor (PPI) --- p.9
Chapter 1.3.4 --- Selective COX-2 Inhibitors --- p.10
Chapter 1.3.4.1 --- GI safety of selective COX-2 inhibitors --- p.11
Chapter 1.3.4.1.1 --- Gastrointestinal outcomes research of rofecoxib --- p.13
Chapter 1.3.4.1.2 --- Celecoxib Long term Arthritis Safety Study --- p.14
Chapter 1.3.4.2 --- Cardiovascular toxicity of NSAIDs --- p.15
Chapter 1.3.4.2.1 --- Cardiovascular toxicity of non-selective NSAIDs --- p.15
Chapter 1.3.4.2.2 --- Cardiovascular toxicity of selective COX-2 inhibitors --- p.16
Chapter 1.4 --- Guidelines on the management of osteoarthritis (OA) and rheumatoid arthritis (RA) --- p.21
Chapter 1.4.1 --- American College of Rheumatology (ACR) Subcommittee --- p.22
Chapter 1.4.2 --- National Institute for Clinical Excellence (NICE) --- p.23
Chapter 1.4.3 --- Hong Kong Hospital Authority (HA) --- p.23
Chapter 1.5 --- Cost of illness of upper GI events in the setting of an emergency room of a regional hospital in Hong Kong and cost analysis of selective COX-2 inhibitor with non-selective NSAID plus gastroprotective agent --- p.24
Chapter 1.6 --- Objectives --- p.25
Chapter Chapter 2 --- Cost of illness of upper GI events in the setting of an emergency room of a regional hospital in Hong Kong --- p.26
Chapter 2.1 --- Methods --- p.28
Chapter 2.1.1 --- Study site --- p.28
Chapter 2.1.2 --- Cohort participants --- p.28
Chapter 2.1.3 --- Resource data collection --- p.29
Chapter 2.1.4 --- Cost data --- p.30
Chapter 2.1.5 --- Statistical Methods --- p.31
Chapter 2.1.6 --- Study perspective --- p.31
Chapter 2.2 --- Results --- p.31
Chapter 2.2.1 --- Demographic data --- p.31
Chapter 2.2.2 --- Total direct medical cost of upper GI complaints in UCH --- p.33
Chapter 2.3 --- Discussion --- p.35
Chapter 2.3.1 --- Total direct medical cost of upper GI events --- p.35
Chapter 2.3.2 --- Cost of upper GI events associated with NSAID usage --- p.38
Chapter 2.3.3 --- Low dose aspirin on NSAID-induced GI toxicity --- p.38
Chapter 2.3.4 --- Limitation --- p.39
Chapter 2.3.5 --- Future study --- p.41
Chapter 2.4 --- Conclusion --- p.41
Chapter Chapter 3 --- Cost analysis of selective COX-2 inhibitor versus non-selective NSAID with gastroprotective agent --- p.43
Chapter 3.1 --- Methods --- p.46
Chapter 3.1.1 --- Local randomized clinical trial --- p.46
Chapter 3.1.1.1 --- Study population --- p.46
Chapter 3.1.1.2 --- Cost data --- p.47
Chapter 3.1.1.3 --- Statistical Methods --- p.48
Chapter 3.1.1.4 --- Sensitivity analysis --- p.49
Chapter 3.1.2 --- Large randomized clinical trial --- p.49
Chapter 3.1.2.1 --- Study population --- p.49
Chapter 3.1.2.2 --- Cost data --- p.50
Chapter 3.2 --- Results --- p.50
Chapter 3.2.1 --- Local randomized clinical trial --- p.51
Chapter 3.2.1.1 --- Demographic data --- p.51
Chapter 3.2.1.2 --- Cost analysis --- p.52
Chapter 3.2.1.3 --- Sensitivity analysis --- p.53
Chapter 3.2.2 --- Large randomized clinical trial --- p.54
Chapter 3.2.2.1 --- Demographic data --- p.54
Chapter 3.2.2.2 --- Cost analysis --- p.55
Chapter 3.3 --- Discussion --- p.55
Chapter 3.3.1 --- Cost analysis --- p.55
Chapter 3.3.2 --- Sensitivity analysis --- p.59
Chapter 3.3.3 --- Low dose aspirin on NSAID-induced GI toxicity --- p.59
Chapter 3.3.4 --- Limitation --- p.60
Chapter 3.4 --- Future study --- p.62
Chapter 3.5 --- Conclusion --- p.62
Chapter Chapter 4 --- Conclusion --- p.63
Chapter Chapter 5 --- Reference --- p.65
Appendix Data collection form --- p.75

A feature extraction approach based on color is firstly proposed. Exploiting color histogram of an image, we can obtain distribution of different colors in images. Then we employ minimum distance classifier based on a new distance criterion to judge status of regions. In this section, we also validate benefits of WCE image enhancement to the proposed CAD system.
Finally, we propose a new approach of chrominance moment as another kind of feature to discriminate normal regions from abnormal regions, which makes full use of Tchebichef polynomials and HSI color space. This new feature extraction scheme preserves illumination invariance without numerical approximation.
In conclusion, this thesis investigates several major and challenging problems such as WCE images enhancement and feature extractions in CAD for WCE images, and proposes several novel schemes to solve those problems. Extensive experiments are reported to demonstrate effectiveness of the proposed algorithms.
Next, we investigate automatic diseases detection for WCE images to partially solve the second problem. In this part we explore different features that are suitable for detection of diseases from three viewpoints, i.e., color, texture and chromaticity, because clinicians mainly use these clues to diagnose. At the same time, we introduce their corresponding classifiers.
We further advance a new texture feature extraction method, curvelet based local binary pattern, to detect abnormal regions in WCE images. This method takes advantage of curvelet transform and local binary pattern to describe textural features of WCE images.
Wireless capsule endoscopy (WCE) is a state-of-the-art technology to diagnose gastrointestinal (GI) tract diseases without invasiveness. However, there exist two major problems concerning WCE images. One problem is that many images for diagnosis have rather low contrast and are noisy, which causes difficulties to diagnosis and also to computer-aided detection, so it is necessary to enhance these images. The other one is that the viewing process of video data per examination is very time consuming because of the great amount of video data. If we can use computerized methods to help the physicians detect some abnormal regions in WCE images, it will certainly reduce the burden of physicians. Focusing on these two goals, this thesis mainly studies some main challenging problems in computer-aided diagnosis (CAD) system for WCE images. To solve the first problem, we put forward an adaptive curvature strength diffusion method to enhance WCE images. Based on local characteristics analysis of WCE images, we propose a new concept of curvature strength. Then, we employ curvature strength diffusion to enhance WCE images with an adaptive choice of conductance parameter. Finally, we extend the curvature strength diffusion to color space since WCE images are color images.
Li, Baopu.
Adviser: Max Q. H. Meng.
Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3640.
Thesis (Ph.D.)--Chinese University of Hong Kong, 2008.
Includes bibliographical references (leaves 126-150).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Abstracts in English and Chinese.
School code: 1307.